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Biomedical subjects

Barry H Greenberg

Publications and source records attributed to Barry H Greenberg.

At least 19 recordsLinked to original sources
PubMed2007

Association between performance measures and clinical outcomes for patients hospitalized with heart failure.

CONTEXT: Assessment of quality of care in heart failure has focused on the development and use of process-based performance measures, with the presumption that these processes are associated with improved clinical outcomes. However, this link remains largely untested. OBJECTIVE: To examine the relationship between current American College of Cardiology/American Heart Association (ACC/AHA) performance measures for patients hospitalized with heart failure and relevant clinical outcomes. DESIGN, SETTING, AND PATIENTS: The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, a registry and performance improvement program for patients hospitalized with heart failure. Sixty- to ninety-day postdischarge follow-up data were prospectively collected from 5791 patients at 91 US hospitals in a prespecified 10% sample between March 2003 and December 2004. Mean patient age was 72.0 years, 51% were male, 78% were white, and 42% had ischemic etiology. Multivariable and propensity-adjusted analyses were performed to assess the process-outcome relationship for each performance measure in eligible patients. Additionally, we evaluated the process-outcome link of a potential performance measure for beta-blockade at discharge among eligible patients hospitalized with heart failure. MAIN OUTCOME MEASURES: Sixty- to ninety-day mortality and combined mortality/rehospitalization rates. RESULTS: Mortality during follow-up was 8.6% and mortality/rehospitalization was 36.2%. None of the 5 ACC/AHA heart failure performance measures was significantly associated with reduced early mortality risk, and only angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use at discharge was associated with 60- to 90-day postdischarge mortality or rehospitalization. Beta-blockade at the time of hospital discharge, currently not a heart failure performance measure, was strongly associated with reduced risk of mortality (hazard ratio, 0.48; 95% confidence interval, 0.30-0.79; P = .004) and mortality/rehospitalization during follow-up. CONCLUSIONS: Current heart failure performance measures, aside from prescription of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at discharge, have little relationship to patient mortality and combined mortality/rehospitalization in the first 60 to 90 days after discharge. Additional measures and better methods for identifying and validating heart failure performance measures may be needed to accurately assess and improve care of patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed2007

Carvedilol use at discharge in patients hospitalized for heart failure is associated with improved survival: an analysis from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF).

BACKGROUND: The IMPACT-HF trial demonstrated that carvedilol use at the time of heart failure (HF) hospital discharge significantly increased 90-day postdischarge treatment rates. Whether there is an early survival benefit associated with this therapeutic approach in patients hospitalized for HF is unknown. We examined the early effects on mortality and rehospitalization of carvedilol use at discharge in patients hospitalized for HF and left ventricular systolic dysfunction (LVSD) compared with outcomes in patients who are eligible for, but do not receive, beta blockers before discharge. METHODS: The OPTIMIZE-HF program enrolled 5791 patients admitted with HF in a web-based registry at 91 hospitals participating with prespecified 60- to 90-day follow-up from March 2003 to December 2004. Outcomes data were prospectively collected on patients eligible for beta-blocker therapy and analyzed according to predischarge beta-blocker use. RESULTS: The mean age was 69.7 years; 63% were male, etiology was ischemic in 52%, and mean left ventricular ejection fraction was 24.3%. A total of 2720 patients had LVSD, among whom 2373 (87.2%) were eligible to receive a beta blocker at discharge and carvedilol was prescribed in 1162 (49.0%). Discharge use of carvedilol was associated with a significant reduction in mortality risk at 60 to 90 days (hazard ratio 0.46, P = .0006) and mortality or rehospitalization (odds ratio 0.71, P = .0175) compared to no predischarge beta blocker. Predischarge use of carvedilol was well tolerated with high rates of continued therapy at 60 to 90 days follow-up. Similar findings were observed for other evidence-based beta blockers. CONCLUSIONS: Carvedilol use at the time of HF hospital discharge is well tolerated, improves treatment rates, and is associated with an early survival benefit. These findings provide further support for guideline recommendations that carvedilol or other evidence-based beta blocker should be initiated before hospital discharge in stable patients with HF and LVSD.

Adrenergic beta-Antagonists↗
PubMed2006

Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure.

CONTEXT: The association between systolic blood pressure (SBP) at admission, clinical characteristics, and outcomes in patients hospitalized for heart failure who have reduced or relatively preserved systolic function has not been well studied. OBJECTIVE: To evaluate the relationship between SBP at admission, clinical profile, and outcomes in patients hospitalized for acute heart failure. DESIGN, SETTING, AND PATIENTS: Cohort study using data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry and performance-improvement program for patients hospitalized with heart failure at 259 US hospitals between March 2003 and December 2004. Patients were divided into quartiles by SBP at hospital admission (<120, 120-139, 140-161, and >161 mm Hg). In-hospital outcomes were based on 48,612 patients aged 18 years or older with heart failure. Of the 41,267 patients with left ventricular function assessed, 21,149 (51%) had preserved left ventricular function. Postdischarge outcomes were based on a prespecified subgroup (n = 5791, 10% of patients) with follow-up data assessed between 60 and 90 days. MAIN OUTCOME MEASURES: In-hospital and postdischarge mortality. RESULTS: Patients with higher SBP were more likely to be female and black and to have preserved systolic function. Fifty percent of the patients had SBP higher than 140 mm Hg at admission. Patients with lower SBP at admission had higher in-hospital and postdischarge mortality rates. Higher SBP at admission was associated with lower in-hospital mortality rates: 7.2% (<120 mm Hg), 3.6% (120-139 mm Hg), 2.5% (140-161 mm Hg), and 1.7% (>161 mm Hg) (P<.001 for overall difference). Postdischarge mortality rates in the follow-up cohort by SBP at admission were 14.0%, 8.4%, 6.0%, and 5.4%, respectively (P<.001 for overall difference). CONCLUSIONS: Systolic hypertension is common in patients hospitalized for heart failure. Systolic blood pressure is an independent predictor of morbidity and mortality in patients with heart failure with either reduced or relatively preserved systolic function. Low SBP (<120 mm Hg) at hospital admission identifies patients who have a poor prognosis despite medical therapy. These findings may have important therapeutic implications because characteristics and outcomes differ greatly among patients with heart failure with varying SBP.

Acute Disease↗
PubMed2006

Pharmacokinetic profile of controlled-release carvedilol in patients with left ventricular dysfunction associated with chronic heart failure or after myocardial infarction.

We compared the pharmacokinetic (PK) profiles of repeated dosing with the currently available immediate-release (IR) carvedilol (given twice daily) and a newly developed controlled-release (CR) formulation (given once daily) in patients with left ventricular dysfunction (LVD). We enrolled 188 patients with stable mild, moderate, or severe heart failure as well as survivors of a recent acute myocardial infarction (MI) with asymptomatic LVD (left ventricular ejection fraction </=0.40) in a crossover study. PK variables were initially assessed after patients had received carvedilol IR 3.125, 6.25, 12.5, or 25 mg twice daily for >/=2 weeks. Patients were then switched to the corresponding dose of carvedilol CR (10, 20, 40, or 80 mg once daily), and PK variables were reassessed after an additional 2 weeks. The primary measures included trough plasma concentration (C(tau)), maximum plasma concentration (C(max)), and area under the concentration-time curve (AUC([0-t])) for both enantiomers of carvedilol of each formulation of the drug. The AUC((0-t)) and the trough and maximum carvedilol concentrations for both the R(+) and S(-) enantiomers were similar when carvedilol IR was compared with carvedilol CR as follows: 3.125 mg twice daily versus 10 mg once daily, 6.25 mg twice daily versus 20 mg once daily, 12.5 mg twice daily versus 40 mg once daily, and 25 mg twice daily versus 80 mg once daily, respectively. Based on a pooled analysis, the AUC((0-t)), C(max), and C(tau) for both R(+) and S(-) were equivalent for the CR and IR formulations, with point estimates and 90% confidence intervals within the bioequivalence limits of 80%-125%. The fluctuation index (the CR-IR ratio for [C(max) - C(min)]/C(ss) where C(min) is the minimum observed concentration over the dosing interval and C(ss) is the concentration at steady state) for both R(+)- and S(-)-carvedilol was approximately 1, indicating that the peak-to-trough fluctuation in plasma concentration for carvedilol after use of carvedilol CR once daily was similar to that for carvedilol IR given twice daily. The median time to maximum observed plasma concentration (t(max)) was approximately 3 hours longer for both enantiomers after administration of carvedilol CR as compared with carvedilol IR. These data demonstrate that the new carvedilol CR formulation given once daily is equivalent to the currently available carvedilol IR formulation given twice daily in patients with heart failure and asymptomatic post-MI LVD.

Adolescent↗
PubMed2006

Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes.

This article describes a meta-analysis of published associations between depression and heart failure (HF) in regard to 3 questions: 1) What is the prevalence of depression among patients with HF? 2) What is the magnitude of the relationship between depression and clinical outcomes in the HF population? 3) What is the evidence for treatment effectiveness in reducing depression in HF patients? Key word searches of the Medline and PsycInfo databases, as well as reference searches in published HF and depression articles, identified 36 publications meeting our criteria. Clinically significant depression was present in 21.5% of HF patients, and varied by the use of questionnaires versus diagnostic interview (33.6% and 19.3%, respectively) and New York Heart Association-defined HF severity (11% in class I vs. 42% in class IV), among other factors. Combined results suggested higher rates of death and secondary events (risk ratio = 2.1, 95% confidence interval 1.7 to 2.6), trends toward increased health care use, and higher rates of hospitalization and emergency room visits among depressed patients. Treatment studies generally relied on small samples, but also suggested depression symptom reductions from a variety of interventions. In sum, clinically significant depression is present in at least 1 in 5 patients with HF; however, depression rates can be much higher among patients screened with questionnaires or with more advanced HF. The relationship between depression and poorer HF outcomes is consistent and strong across multiple end points. These findings reinforce the importance of psychosocial research in HF populations and identify a number of areas for future study.

Cardiac Output, Low↗
PubMed2006

COMPARE: comparison of the effects of carvedilol CR and carvedilol IR on left ventricular ejection fraction in patients with heart failure.

Left ventricular ejection fraction (LVEF) is an important measure of ventricular function in the evaluation of heart failure. Immediate-release (IR) carvedilol twice daily has been shown to improve LVEF in subjects with ischemic and nonischemic chronic heart failure. A once-daily formulation, controlled-release (CR) carvedilol, is expected to improve quality of care through improved adherence as a result of the reduced frequency of dosing. This multicenter, randomized, double-blind study in subjects with stable chronic heart failure will compare the change in LVEF in patients receiving carvedilol IR with those receiving carvedilol CR. LVEF will be measured by 2-dimensional echocardiography at 6 months after entry into the maintenance period of the study drug. The secondary objectives of this study are to assess changes in left ventricular remodeling and function, to evaluate changes in brain natriuretic peptide levels, and to determine the incidence of all-cause and heart failure-related hospitalizations and all-cause mortality after treatment with carvedilol CR or carvedilol IR.

Administration, Oral↗
PubMed2006

Utility of impedance cardiography for the identification of short-term risk of clinical decompensation in stable patients with chronic heart failure.

OBJECTIVES: This study sought to assess the potential utility of impedance cardiography (ICG) in predicting clinical deterioration in ambulatory patients with heart failure (HF). BACKGROUND: Impedance cardiography uses changes in thoracic electrical impedance to estimate hemodynamic variables, but its ability to predict clinical events has not been evaluated. METHODS: We prospectively evaluated 212 stable patients with HF and a recent episode of clinical decompensation who underwent serial clinical evaluation and blinded ICG testing every 2 weeks for 26 weeks and were followed up for the occurrence of death or worsening HF requiring hospitalization or emergent care. RESULTS: During the study, 59 patients experienced 104 episodes of decompensated HF (16 deaths, 78 hospitalizations, and 10 emergency visits). Multivariate analysis identified 6 clinical and ICG variables that independently predicted an event within 14 days of assessment. These included three clinical variables (visual analog score, New York Heart Association functional class, and systolic blood pressure) and three ICG parameters (velocity index, thoracic fluid content index, and left ventricular ejection time). The three ICG parameters combined into a composite score was a powerful predictor of an event during the next 14 days (p = 0.0002). Visits with a high-risk composite score had 2.5 times greater likelihood and those with a low-risk score had a 70% lower likelihood of a near-term event compared with visits at intermediate risk. CONCLUSIONS: These results suggest that when performed at regular intervals in stable patients with HF with a recent episode of clinical decompensation, ICG can identify patients at increased near-term risk of recurrent decompensation.

Adult↗
PubMed2005

Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects.

ANG-(1-7) improves the function of the remodeling heart. Although this peptide is generated directly within the myocardium, the effects of ANG-(1-7) on cardiac fibroblasts that play a critical role in cardiac remodeling are largely unknown. We tested the hypothesis that specific binding of ANG-(1-7) to cardiac fibroblasts regulates cellular functions that are involved in cardiac remodeling. 125I-labeled ANG-(1-7) binding assays identified specific binding sites of ANG-(1-7) on adult rat cardiac fibroblasts (ARCFs) with an affinity of 11.3 nM and a density of 131 fmol/mg protein. At nanomolar concentrations, ANG-(1-7) interacted with specific sites that were distinct from ANG II type 1 and type 2 receptors without increasing cytosolic Ca2+ concentration. At these concentrations, ANG-(1-7) had inhibitory effects on collagen synthesis as assessed by [3H]proline incorporation and decreased mRNA expression of growth factors in ARCFs. These effects of ANG-(1-7) contrasted with effects of ANG II. Pretreatment of ARCFs with ANG-(1-7) inhibited ANG II-induced increases in collagen synthesis and in mRNA expression of growth factors, including endothelin-1 and leukemia inhibitory factor. ANG-(1-7) pretreatment also inhibited the stimulatory effects of conditioned medium from ANG II-treated ARCFs on [3H]leucine incorporation and atrial natriuretic factor mRNA expression, markers of hypertrophy, in cardiomyocytes. Thus ANG-(1-7) interacted with specific receptors on ARCFs to exert potential antifibrotic and antitrophic effects that could reverse ANG II effects. These results suggest that ANG-(1-7) may play an important role in the heart in regulating cardiac remodeling.

Angiotensin I↗
PubMed2005

Effects of cytokine treatment on angiotensin II type 1A receptor transcription and splicing in rat cardiac fibroblasts.

Angiotensin II (ANG II) plays important roles in cardiac extracellular matrix remodeling via its type 1A (AT(1A)) receptor. The cytokines tumor necrosis factor-alpha and interleukin-1beta (IL-1beta) were shown previously to upregulate AT(1A) receptor mRNA and protein, thereby increasing the profibrotic response to ANG II in cardiac fibroblasts. The present experiments implicate increased nuclear factor-kappaB (NF-kappaB)-dependent transcription and also, to a lesser extent, altered mRNA splicing in the mechanism of receptor upregulation. Cytokine stimulation was found to increase AT(1A) heterogeneous nuclear RNA levels, which strongly suggests that mRNA upregulation occurs transcriptionally. The transcription factor NF-kappaB was previously deemed necessary for cytokine-induced AT(1A) receptor mRNA upregulation. Computer analysis of upstream DNA sequences revealed putative NF-kappaB elements at -365 and -2540 bp. Both isolated elements were shown to bind NF-kappaB (using gel-shift assays) and to transactivate a minimal promoter (using reporter assays), although the element at -365 bp appeared stronger. Three splice variants of AT(1A) receptor mRNA that have different 5' untranslated regions were detected in rat tissues, namely, exons 1-2-3 (predominant), 1-2-3+6, and 1-3. Cytokine treatment of fibroblasts upregulated all splice variants, but exon 1-3 increased more than the others. This differential upregulation, albeit of modest magnitude, was statistically significant with IL-1beta treatment. Exon 2 contains an inhibitory minicistron and a predicted inhibitory hairpin structure. Luciferase reporter assays indicated that each splice variant translates at a different efficiency, with exon 1-2-3+6 (both minicistron and hairpin) < exon 1-2-3 (minicistron only) < exon 1-3 (neither minicistron or hairpin). These results provide evidence that cytokines increase AT(1) protein levels by altering both transcription and splicing.

Animals↗
PubMed2005

Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling.

OBJECTIVE: Persistently elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)alpha after acute myocardial infarction (MI) may contribute to maladaptive ventricular remodeling. The aim of the present study was to examine the effects of immunomodulatory therapy with recombinant soluble TNF receptor (TNFR:Fc) or intravenous immunoglobulin (IVIg) on left and right ventricular post-MI remodeling in rats. METHODS AND RESULTS: Adult male Sprague-Dawley rats were subjected to MI by left coronary artery ligation and randomized to treatment with vehicle, TNFR:Fc, or IVIg and sacrificed after 7 days. The main findings were that: (i) TNFR:Fc- and IVIg-treated rats developed less right ventricular (RV) hypertrophy compared to vehicle-treated controls. (ii) LV and arterial pressures in post-MI rats were not affected by the TNFR:Fc or IVIg treatment. (iii) As determined by real-time RT-PCR, both treatments reduced the expression of the hypertrophy-related genes, atrial natriuretic peptide and the ratio of beta/alpha-myosin heavy chains, and genes related to extracellular matrix remodeling (i.e., collagens I and III, matrix metalloproteinase [MMP]-2 and its tissue inhibitor TIMP-1) in the non-ischemic segment of LV and, in particular, in the RV. (iv) Treatment with IVIg, but not TNFR:Fc, reduced MMP-2 zymographic activity in the RV and the expression of genes for TNFalpha and monocyte chemoattractant protein-1. CONCLUSION: Therapy targeted directly against TNFalpha (i.e., TNFR:Fc) and a more general immunomodulatory approach (i.e., IVIg) in the acute phase of MI attenuates the cardiac remodeling process and expression of genes that are involved. These findings raise the possibility that initiation of immunomodulatory therapy post-MI could be beneficial in preventing the later development of heart failure.

Animals↗
PubMed2005

IL-1beta and TNF-alpha upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart.

Angiotensin (Ang) II plays an important role in post-myocardial infarction (MI) cardiac remodeling. The Ang II type 1 (AT(1)) receptor which mediates most Ang II effects is upregulated on non-myocytes in the post-MI heart. We have shown that pro-inflammatory cytokines increase AT(1) receptor density on cardiac fibroblasts through a mechanism involving NF-kappaB activation. This study examines the in vitro kinetics of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) induced AT(1) receptor upregulation in neonatal rat cardiac fibroblasts and assesses temporal and spatial associations between the appearance of these agents and increased AT(1) receptor density post-MI. The results show that IL-1beta more rapidly induces AT(1) receptor upregulation than does TNF-alpha, an effect that can be mimicked by a NF-kappaB-dependent luciferase reporter gene. Moreover, the effects of these pro-inflammatory cytokines are additive. Using immunohistochemistry in the post-MI rat heart we found strong temporal and spatial correlations between TNF-alpha, IL-1beta and AT(1) receptor proteins in the peri-infarction (PI) zone in fibroblasts and macrophages. Labeling intensity for the cytokines and the AT(1) receptor increased from 1 to 7 days post-MI in the PI zone in conjunction with replacement scar formation. This labeling persisted in non-myocytes bordering the scar for up to 83 days post-MI. These findings suggest that IL-1beta and TNF-alpha act coordinately to increase AT(1) receptor density on non-myocytes in the post-MI heart and that this effect may contribute to extracellular matrix remodeling and fibrosis.

Animals↗
PubMed2004

Cardiac resynchronization therapy: caveat medicus!

The device era in heart failure has been heralded by successes in the realm of pacemakers, implantable defibrillators, and ventricular assist devices. In particular, the concept of cardiac resynchronization therapy, which seeks to optimize ventricular contractility by decreasing areas of focal dyssynchrony, is gaining wide acceptance. Recent trials of cardiac resynchronization therapy have suggested that this treatment modality yields benefits that are reflected in improved functional capacity, reversal of ventricular modeling, and decreased hospitalizations. Cardiac resynchronization device therapy exerts a substantial placebo effect, with evidence of improved functional capacity and quality-of-life parameters in almost half of those in the control group, probably as a result of device implantation. Furthermore, analysis of the different trials suggests heterogeneity of response (differences in magnitude of observed benefit between trials presumably enrolling similar heart-failure populations) and a large non-responder rate (no improvement in functional capacity and well-being). The appropriate approach to resynchronization must include much more than simple characteristics of device implantation. We must detect the presence and precise location of mechanical dyssynchrony and be able to find the technical location and place the pacing leads in the appropriate position. Finally, we must be able to show evidence for sustained improvement in ventricular dyssynchrony. Thus, the current approach to resynchronization represents a "best guess" approach to achieving resynchronization by observation of surrogate responses. Continued investigation to determine optimal approaches for achieving a beneficial clinical response is essential to ensure that cardiac resynchronization therapy is offered to those most likely to benefit.

Clinical Trials as Topic↗
PubMed2002

Tumor necrosis factor-alpha-induced AT1 receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis.

Extracellular matrix (ECM) remodeling after myocardial infarction (MI) is an important determinant of cardiac function. Tumor necrosis factor-alpha (TNF-alpha) and angiotensin (Ang) II levels increase after MI and both factors affect fibroblast functions. The type 1 (AT1) receptor that mediates most Ang II effects is upregulated after MI in cardiac fibroblasts, and there is evidence that this is caused by TNF-alpha. We sought to determine if TNF-alpha-induced AT1 receptor upregulation alters fibroblast responsiveness to Ang II and if this effect differs from direct TNF-alpha effects on fibroblast functions. In cultured neonatal rat cardiac fibroblasts, TNF-alpha reduced cellular [3H]-proline incorporation, increased matrix metalloproteinase-2 (MMP-2) activity and protein, and increased TIMP-1 protein levels. In cardiac fibroblasts with TNF-alpha-induced AT1 receptor upregulation, Ang II-stimulated [3H]proline incorporation and TIMP-1 protein production was approximately 2-fold greater than in nonpretreated fibroblasts. Angiotensin II reduced MMP-2 activity and protein level only in TNF-alpha-pretreated fibroblasts. Angiotensin II effects were inhibited by selective AT1 (but not AT2) receptor blockers. Thus, TNF-alpha-induced AT1 receptor upregulation enhances Ang II-mediated functions that favor fibrosis. These effects are mostly directionally opposite of direct TNF-alpha effects on cardiac fibroblasts. Recognition of multifaceted TNF-alpha effects provides new insights into post-MI ECM remodeling.

Angiotensin II↗