Anita Deswal

Cytokines and Cytokine Receptors in Advanced Heart Failure

Background—Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure. Methods and Results—We analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure. This analysis constitutes the largest analysis of cytokines and cytokine receptors to date. Analysis of the patients receiving placebo showed that increasing circulating levels of TNF, interleukin-6, and the soluble TNF receptors were associated with increased mo...

Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

BACKGROUND Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Safety and Efficacy of a Soluble P75 Tumor Necrosis Factor Receptor (Enbrel, Etanercept) in Patients With Advanced Heart Failure

BACKGROUND Although previous studies suggested that TNF may contribute to heart failure progression, it is unclear whether antagonizing TNF is beneficial in heart failure patients. METHODS AND RESULTS Eighteen NYHA class III heart failure patients were randomized into a double-blind dose-escalation study to examine the safety and potential efficacy of etanercept, a specific TNF antagonist (Enbrel). Patients received placebo (6 patients) or an escalating dose (1, 4, or 10 mg/m2) of etanercept (12 patients) given as a single intravenous infusion. Safety parameters and patient functional status were assessed at baseline and at days 1, 2, 7, and 14. There were no significant side effects or clinically significant changes in laboratory indices. There was, however, a decrease in TNF bioactivity and a significant overall increase in quality-of-life scores, 6-minute walk distance, and ejection fraction in the cohort that received 4 or 10 mg/m2 of etanercept; there was no significant change in these parameters in the placebo group. CONCLUSIONS A single intravenous infusion of etanercept was safe and well tolerated in patients with NYHA class III heart failure. These studies provide provisional evidence that suggests that etanercept is sufficient to lower levels of biologically active TNF and may lead to improvement in the functional status of patients with heart failure.

Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction

OBJECTIVES The aim of this study was to evaluate the prevalence and prognostic impacts of noncardiac comorbidities in patients with heart failure (HF) with preserved ejection fraction (HFpEF) compared with those with HF with reduced ejection fraction (HFrEF). BACKGROUND There is a paucity of information on the comparative prognostic significance of comorbidities between patients with HFpEF and those with HFrEF. METHODS In a national ambulatory cohort of veterans with HF, the comorbidity burden of 15 noncardiac comorbidities and the impacts of these comorbidities on hospitalization and mortality were compared between patients with HFpEF and those with HFrEF. RESULTS The cohort consisted of 2,843 patients with HFpEF and 6,599 with HFrEF with 2-year follow-up. Compared with patients with HFrEF, those with HFpEF were older and had higher prevalence of chronic obstructive pulmonary disease, diabetes, hypertension, psychiatric disorders, anemia, obesity, peptic ulcer disease, and cancer but a lower prevalence of chronic kidney disease. Patients with HFpEF had lower HF hospitalization, higher non-HF hospitalization, and similar overall hospitalization compared with those with HFrEF (p < 0.001, p < 0.001, and p = 0.19, respectively). An Increasing number of noncardiac comorbidities was associated with a higher risk for all-cause admissions (p < 0.001). Comorbidities had similar impacts on mortality in patients with HFpEF compared with those with HFrEF, except for chronic obstructive pulmonary disease, which was associated with a higher hazard (1.62 [95% confidence interval: 1.36 to 1.92] vs. 1.23 [95% confidence interval: 1.11 to 1.37], respectively, p = 0.01 for interaction) in patients with HFpEF. CONCLUSIONS There is a higher noncardiac comorbidity burden associated with higher non-HF hospitalizations in patients with HFpEF compared with those with HFrEF. However, individually, most comorbidities have similar impacts on mortality in both groups. Aggressive management of comorbidities may have an overall greater prognostic impact in HFpEF compared to HFrEF.

Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial

IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.

Classification of Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study: A Comparison of Diagnostic Criteria

Background—Population-based research on heart failure (HF) is hindered by lack of consensus on diagnostic criteria. Framingham (FRM), National Health and Nutrition Examination Survey (NHANES), Modified Boston (MBS), Gothenburg (GTH), and International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) code criteria, do not differentiate acute decompensated heart failure (ADHF) from chronic stable HF. We developed a new classification protocol for identifying ADHF in the Atherosclerosis Risk in Communities (ARIC) Study and compared it with these other schemes. Methods and Results—A sample of 1180 hospitalizations with a patient address in 4 study communities and eligible discharge codes were selected. After assessing whether the chart contained evidence of possible HF signs, 705 were fully abstracted. Two independent reviewers classified each case as ADHF, chronic stable HF, or no HF, using ARIC classification guidelines. Fifty-nine percent of cases met ARIC criteria for ADHF and 13.9% and 27.1% were classified as chronic stable HF or no HF, respectively. Among events classified as HF by FRM criteria, 68.4% were validated as ADHF, 9.6% as chronic stable HF, and 21.9% as no HF. However, 92.5% of hospitalizations with a primary ICD-9-CM 428 “heart failure” code were validated as ADHF. Sensitivities of comparison criteria to classify ADHF ranged from 38–95%, positive predictive values from 62–92%, and specificities from 19–96%. Conclusions—Although comparison criteria for classifying HF were moderately sensitive in identifying ADHF, specificity varied when applied to a randomly selected set of suspected HF hospitalizations in the community.

Biomarkers of inflammation in heart failure.

Heart failure (HF) is characterized by the elaboration of a portfolio of pro-inflammatory cytokines and inflammatory mediators that are considered to contribute to disease progression by virtue of the deleterious effects that these molecules exert on the heart and circulation. Recent studies have suggested that these inflammatory mediators may serve as relevant markers of disease severity and HF prognosis. Moreover, there is evidence that changes in the levels of inflammatory biomarkers may prove useful in following the change in patient clinical status following institution of appropriate HF therapy. This review will focus on the emerging role of inflammatory biomarkers, including pro-inflammatory cytokines, C-reactive protein, and erythrocyte sedimentation rate in patients with HF.

Relationship of Hemoglobin A1C and Mortality in Heart Failure Patients With Diabetes

OBJECTIVES This study was designed to examine the relationship between glycosylated hemoglobin (HbA1C) and adverse outcomes in diabetic patients with established heart failure (HF). BACKGROUND Despite the common coexistence of diabetes and HF, previous studies examining the association between HbA1C and outcomes in this population have been limited and have reported discrepant results. METHODS We assessed the association between increasing quintiles (Q1 to Q5) of HbA1C and risk of death or risk of HF hospitalization by conducting a retrospective study in a national cohort of 5,815 veterans with HF and diabetes treated in ambulatory clinics at Veterans Affairs medical centers. RESULTS At 2 years of follow-up, death occurred in 25% of patients in Q1 (HbA1C < or =6.4%), 23% in Q2 (6.4% < HbA1c < or =7.1%), 17.7% in Q3 (7.1% < HbA1c < or =7.8%), 22.5% in Q4 (7.8% < HbA1c < or =9.0%), and 23.2% in Q5 (HbA1c >9.0%). After adjustment for potential confounders, the middle quintile (Q3) had reduced mortality when compared with the lowest quintile (risk-adjusted hazard ratio: 0.73, 95% confidence interval: 0.61 to 0.88, p = 0.001). Hospitalization rates for HF at 2 years increased with increasing quintiles of HbA1C (Q1: 13.3%, Q2: 13.1%, Q3: 15.5%, Q4: 16.4%, and Q5: 18.2%), but this association was not statistically significant when adjusted for potential confounders. CONCLUSIONS The association between mortality and HbA1C in diabetic patients with HF appears U-shaped, with the lowest risk of death in those patients with modest glucose control (7.1% < HbA1C < or =7.8%). Future prospective studies are necessary to define optimal treatment goals in these patients.

The role of cytokines in disease progression in heart failure.

Recent studies have identified the importance of biologically active molecules such as neurohormones as mediators of disease progression in heart failure. More recently it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggests that the cytokines, much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.

An overview of tumor necrosis factor α and the failing human heart

Recent studies have identified the importance of biologically active molecules (e.g., neurohormones) in disease progression in heart failure. In addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggest that the cytokines (e.g., tumor necrosis factor alpha), much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.