ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with ...functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study-a multicenter, randomized study of exercise training in HF.
HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II to IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6-31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio, 1.48; P<0.0001), cardiovascular death or HF hospitalization (hazard ratio, 2.14; P<0.0001), and all-cause mortality (hazard ratio, 2.33; P<0.0001; all hazard ratios for log2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro-B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement.
ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory patients with HF although it did not significantly affect reclassification of risk.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.
Chronic heart failure remains a major cause of mortality and morbidity. The role of antithrombotic therapy in patients with chronic heart failure has long been debated. The objective of this study ...was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm.
This prospective, randomized clinical trial of open-label warfarin (target international normalized ratio of 2.5 to 3.0) and double-blind treatment with either aspirin (162 mg once daily) or clopidogrel (75 mg once daily) had a 30-month enrollment period and a minimum of 12 months of treatment. We enrolled 1587 men and women >/=18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of </=35%. The primary outcome was the time to first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke. For the primary composite end point, the hazard ratios were as follows: for warfarin versus aspirin, 0.98 (95% CI, 0.86 to 1.12; P=0.77); for clopidogrel versus aspirin, 1.08 (95% CI, 0.83 to 1.40; P=0.57); and for warfarin versus clopidogrel, 0.89 (95% CI, 0.68 to 1.16; P=0.39). Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel. Hospitalization for worsening heart failure occurred in 116 (22.2%), 97 (18.5%), and 89 (16.5%) patients treated with aspirin, clopidogrel, and warfarin, respectively (P=0.02 for warfarin versus aspirin).
The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin.
Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device therapies targeting sudden cardiac death (SCD). Contemporary estimates of SCD risk after ...hospitalization for heart failure are limited. We describe the incidence, timing, and clinical predictors of SCD after hospitalization for HFrEF (≤40%) in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial. Multiple logistic regression analyses tested >30 baseline covariates (including treatment randomization, demographics, comorbid conditions, natriuretic peptides, ejection fraction, and medical and device therapies) to identify predictors of 1-year SCD. Of the 4,024 trial patients discharged alive (97%), there were 268 who experienced SCD (7%) and 703 who experienced non-SCD (17%) during median follow-up of 9.9 months. Implantable cardioverter defibrillator use at baseline was 14.5%. Estimates of SCD at 1, 3, 6, and 12 months were 0.8%, 2.3%, 4.1%, and 7.4%, respectively. Most patients were readmitted before SCD (n = 147, 55%). Male gender, black race, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were potential predictors of 1-year SCD after hospitalization for HFrEF (all p <0.10); however, this final model demonstrated poor discrimination (C-statistic 0.57). In conclusion, in the EVEREST trial, patients hospitalized for HFrEF faced risks of 1-year postdischarge SCD of 7%, which accrued gradually over time, and were balanced with high competing risks of nonsudden death (17%). Traditional clinical characteristics fail to adequately predict SCD risk. Further data are needed to identify patients at greatest relative risk for SCD (compared with non-SCD) after hospitalization for HFrEF.
Improvements in the treatment of ischemic heart disease have led to a significant growth in the numbers of patients with systolic heart failure secondary to myocardial injury. Current therapies fail ...to address the loss of contractile tissue due to myocardial injury. Cell therapy is singular in its promise of primarily treating this underlying issue through salvage of viable myocardium or generation of new contractile tissue. Multiple cell types have been used to target acute myocardial infarction, chronic ischemic heart disease and heart failure due to infarction. Bone marrow mononuclear cells have been used to increase myocardial salvage after acute infarction. Randomized trials of over 800 patients have demonstrated no safety issues, and meta-analyses have suggested an improvement in left ventricular function in treated patients with trends toward improvements in hard cardiac end points. Cell therapy for chronic ischemic heart disease with bone marrow angiogenic progenitors has shown similar safety and trends toward improvement in function. While these therapies have targeted patients with viable myocardium, myoblasts have been used to treat patients with left ventricular dysfunction secondary to transmural infarction. Cell types with cardiomyogenic potential, including induced pluripotent stem cells and cardiac progenitor cells, offer the promise of true myocardial regeneration. Future studies with these cells may open the door for true myocardial regeneration.
Abstract Background Although sex-based disparities in use of guideline-recommended heart failure (HF) therapies have been described, little is known about whether performance improvement (PI) ...initiatives produce equitable improvements in guideline-recommended therapies. Methods and Results IMPROVE HF is a prospective study of a practice-based PI intervention in patients with systolic HF or post–myocardial infarction left ventricular dysfunction. Mean changes from baseline to 24 months after intervention were compared between women and men for treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, aldosterone antagonists, anticoagulation for atrial fibrillation, cardiac resynchronization therapy (CRT), implantable cardioverter-defibrillator (ICD), and HF education. This analysis included 15,170 patients at 167 cardiology practices (4,383 28.9% women, 10,787 71.1% men). At baseline, women were less likely than men to be treated with anticoagulation and ICD. Significant improvements in 6 of 7 quality measures were evident at 24 months for both sexes. The absolute magnitude of improvement was similar for 5 measures and significantly better in women for CRT, ICD, and composite care. Conclusions This PI intervention was associated with similar or greater increases in use of guideline-recommended HF therapies for eligible women compared with men. Clinical decision support and performance feedback may help to ensure improved, equitable care for men and women with HF. Clinical Trial Registration Information http://www.clinicaltrials.gov unique identifier: NCT00303979.
Over several decades, a large body of evidence has emerged to suggest that depressive disorder is a risk factor for heart diseases, both aetiologically and prognostically. Several large, prospective, ...longitudinal studies have examined the relationship between depression and the development of coronary artery disease (CAD); they reveal that the relationship is significant and independent of conventional risk factors. Prognostic studies have shown that depression is associated with two to three times higher mortality after myocardial infarction, unstable angina or coronary artery bypass grafting, and in patients with stable CAD compared with such patients without depression. Depression also has been found to increase mortality and morbidity in patients with heart failure, regardless of its aetiology. Such adverse associations persist after adjustment for conventional prognostic risk factors. Despite all of these findings, depressed patients with heart disease are less likely to be recognised clinically as being depressed than those patients who have depression but no heart disease. The very limited evidence available from pharmacological clinical trials raises concern about the safety of antidepressants in CAD and heart failure. In addition, no research has addressed whether the treatment of depression in patients with heart disease will improve their prognosis.
Recently, clinical depression has been identified as an independent risk factor for increased mortality in patients following acute coronary events. Although the underlying mechanisms of this link ...remain uncertain, increased platelet activity has been suggested but never proven as the mechanism responsible for this association. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI), and is an effective antidepressant agent. Its major liver metabolite, N-desmethylsertraline (NDMS), is known to be neurologically inactive. We assessed the in vitro effects of escalating concentrations of sertraline and NDMS on human platelets by aggregometry in plasma and whole blood, by expression of major surface receptors with flow cytometry in washed cells and in the whole blood, and quantitatively by various platelet function analysers in healthy volunteers and patients with coronary artery disease. Pretreatment of blood samples with sertraline and NDMS resulted in a dose-dependent inhibition of platelet-rich plasma aggregation induced by 5 μ M ADP (P=, 0.002), by 10 μ M ADP (P= 0.0017), by collagen (P= 0.008), and by thrombin (P= 0.026). Whole blood platelet aggregability was also significantly reduced when induced by 20 μ M ADP (P= 0.006), and by collagen (P= 0.01). Surface expression of CD9 (P= 0.004), GP Ib (P= 0.0001), GP IIb/IIIa (P= 0.007), VLA-2 (P= 0.01), P-selectin (P= 0.02), and PECAM-1 (P= 0.01), but not the vitronectin receptor, was also reduced in sertraline and NDMS pretreated washed platelets. Whole blood flow cytometry revealed significant inhibition of GP IIb/IIIa (P= 0.008), and P-selectin expression (P= 0.0001) in NDMS treated samples. Closure time was delayed for the collagen-ADP cartridge (P= 0.009), and for the collagen-epinephrin cartridge (P= 0.01), indicating platelet inhibition in whole blood under high shear conditions. Rapid platelet-function assay revealed a decreased (P= 0.002) ability of platelets to agglutinate fibrinogen-coated beads, suggesting GP IIb/IIIa inhibition. Both sertraline, and its neurologically inactive metabolite NDMS, exhibited significant dose-dependent inhibition of human platelets. The documented anti-platelet effects of sertraline and NDMS may be directly related to the mortality benefits of SSRIs after ischemic events including myocardial infarction and stroke.
Background Conflicting data exist regarding a potential deleterious association between aspirin (ASA) and angiotensin-converting enzyme inhibitors (ACEIs) when used concurrently in patients with ...heart failure (HF). How such an interaction may be influenced by underlying etiology of HF and whether it extends to patients treated with angiotensin receptor blockers (ARBs), however, are not known. Methods Eligible patients from the OPTIMIZE-HF registry were dichotomized into those with ischemic or nonischemic HF. Potential associations between ASA and ACEI or ARB use and 60- to 90-day postdischarge outcomes were assessed using Cox proportional and logistic regression modeling. Models were adjusted for factors known to influence the outcome of interest and by propensity score for ACEI or ARB prescription after an index HF admission. Results Mortality was not increased (hazard ratio 95% CI) when ASA was used in conjunction with ACEI (0.51 0.29-0.87) or ARB (0.29 0.09-0.96) in patients with ischemic or nonischemic (ACEI 0.71 0.42-1.21, ARB 1.42 0.74-2.74) HF. Regression model parameter estimates trended toward harm reduction, but interaction terms for mortality and a composite of mortality or rehospitalization were nonsignificant ( P for all >.05). Conclusions When combined with ACEI or ARB, ASA had no demonstrable adverse effect on intermediate-term postdischarge outcomes for patients with ischemic or nonischemic HF.
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