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Biomedical subjects

A Deswal

Publications and source records attributed to A Deswal.

12 recordsLinked to original sources
PubMed2001

Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST).

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 mortality. In men, there was a linear increase in circulating levels of TNF with advancing age. Women < or = 50 years of age had relatively low levels of TNF, but TNF levels were disproportionately higher in women >50 years of age. No differences existed in cytokines and/or cytokine receptors in whites versus nonwhites, and circulating levels of cytokines and cytokine receptors were significantly greater in patients with ischemic heart disease. CONCLUSIONS: Cytokines and cytokine receptors are independent predictors of mortality in patients with advanced heart failure. Moreover, circulating levels of cytokines are modified by age, sex, and cause of heart failure.

Adult↗
PubMed2001

Trials within trials: confirmatory subgroup analyses in controlled clinical experiments.

Subgroup analyses remain a popular and necessary component of controlled clinical trials. However, lack of prospective specification, inadequate sample size, inability to maintain power, and the cumulative effect of sampling error can complicate their interpretation. This article demonstrates that clinical trial design tools that would allow the medical community to draw confirmatory and not just exploratory conclusions from specific subgroup evaluations are available to methodologists. Distinct from the use of a treatment by subgroup interaction term, this methodology provides an evaluation of the effect of an intervention within a particular subgroup stratum prospectively declared to be of interest to the investigators. The necessary prespecification of stratum-specific type I error rates, when combined with (1) a stratum-specific event rate in the subgroup, (2) a stratum-specific primary endpoint, (3) a stratum-specific endpoint precision, and/or (4) a stratum-specific efficacy, satisfies the requirements for a subgroup stratum's "stand-alone" interpretation at the trial's conclusion.

Clinical Trials as Topic↗
PubMed2001

The role of anti-cytokine therapy in the failing heart.

The understanding of the role of "neurohormones" in the progression of heart failure has led to the utilization of agents that antagonize the activation of neurohormonal systems as effective therapy in patients with heart failure. As more evidence emerges linking proinflammatory cytokines to disease progression in heart failure, there is an increasing interest in developing anti-cytokine strategies that might be used as adjunctive therapy in patients with heart failure. Accordingly, the focus of the present review is to summarize the experimental and clinical studies that have attempted to modulate the effects of cytokines in heart failure. Strategies have been employed to either suppress cytokine production or to prevent their toxic effects by interfering with the binding of cytokines to their cognate receptors.

Cytokines↗
PubMed2001

Effects of vesnarinone on peripheral circulating levels of cytokines and cytokine receptors in patients with heart failure: a report from the Vesnarinone Trial.

STUDY OBJECTIVES: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST). METHODS: Circulating levels of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327). RESULTS: Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period. CONCLUSIONS: In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure.

Cardiotonic Agents↗
PubMed2001

Experimental options in the treatment of heart failure: the role of cytokine antagonism.

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 will review recent clinical material that suggests that tumor necrosis factor, a pro-inflammatory cytokine, may contribute to disease progression in heart failure by virtue of the direct toxic effects that this molecule exerts on the heart and circulation. In addition, this article reviews the existing clinical literature, which suggests that cytokine antagonism is safe and potentially effective in patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed1999

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.

Aged↗
PubMed1999

An overview of tumor necrosis factor alpha 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.

Gene Expression Regulation↗
PubMed1998

Quantification of the myocardial response to low-dose dobutamine using tissue Doppler echocardiographic measures of velocity and velocity gradient.

Low-dose dobutamine echocardiography has been clinically useful in myocardial viability studies, although routine visual assessment of wall motion is subjective. The objective was to quantify the incremental myocardial response to low-dose dobutamine infusion using a new semiautomated tissue Doppler (TD) analysis system and to compare these data with routine echocardiographic measures in the same subjects. Twelve subjects had TD and routine echocardiographic studies at baseline and during 10-minute stages of dobutamine infusion at 1, 2, 3, and 5 microg/kg/min. Color TD video data were converted to a digital velocity matrix (4.5 velocity data points/mm at 500 Hz) for analysis of mitral annular velocity, endocardial velocity, and velocity gradient at each stage. Posterior wall percent thickening and ejection fraction were calculated from the routine images. Mitral annular peak systolic velocity significantly increased with only 1 microg/kg/min of dobutamine from 69 +/- 9 to 77 +/- 7 mm/s (p <0.05 vs baseline), and further incremental increases occurred with each subsequent dose. Anteroseptal and posterior wall peak endocardial velocity increased with 2 microg/kg/min of dobutamine from 33 +/- 7 to 46 +/- 15 mm/s and 50 +/- 9 to 61 +/- 10 mm/s, respectively (p <0.01 vs baseline) and further increased with 5 microg/kg/min (p <0.0001 vs 3 microg/kg/min). Posterior wall peak systolic gradient also increased with 2 microg/kg/min of dobutamine from 3.1 +/- 0.6 to 5.4 +/- 1.6 s(-1) (p <0.05 vs baseline). Routine measures of percent wall thickening or ejection fraction did not detect increases until the 3 microg/kg/min dose. TD can detect subtle alterations in contractility induced by low-dose dobutamine and has the potential to quantify regional ventricular function objectively.

Adrenergic beta-Agonists↗
PubMed1997

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.

Animals↗
PubMed1996

Cardiac involvement in scleroderma.

In summary, cardiac involvement in systemic sclerosis can be manifested as myocardial disease, pericardial disease, conduction system disease, or arrhythmias. Clinical cardiac involvement is a poor prognostic factor. Asymptomatic cardiac abnormalities are frequent, and all cardiac abnormalities are seen more often in diffuse scleroderma. Unlike other organs, the role of vascular involvement is unclear. At present, treatment of cardiac scleroderma is essentially symptomatic and empiric. The role of vasodilation and immunosuppression needs further exploration.

Arrhythmias, Cardiac↗