Showing papers by "Arthur M. Feldman published in 2004"

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.

Abstract: background We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays. methods A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting–enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker–defibrillator. The primary composite end point was the time to death from or hospitalization for any cause. results As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker–defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker–defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker–defibrillator reduced the risk by 36 percent (P=0.003). conclusions In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.

Targeted Anticytokine Therapy in Patients with Chronic Heart Failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL)

Abstract: Background— Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. Methods and Results— Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction ≤0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE ( P =0.17) or RECOVER ( P =0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P =0.33). Conclusions— The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.

Use of a wearable defibrillator in terminating tachyarrhythmias in patients at high risk for sudden death: results of the WEARIT/BIROAD.

Abstract: The automatic ICD improves survival in patients with a history of sudden cardiac arrest. However, some patients do not meet the guidelines for ICD implantation or are unable to receive an implantable device. This study tested the hypothesis that these patients could benefit from a wearable cardioverter defibrillator. Patients with symptomatic heart failure and an ejection fraction of <0.30 (WEARIT Study) or patients having complications associated with high risk for sudden death after a myocardial infarction or bypass surgery not receiving an ICD for up to 4 months (BIROAD Study) were enrolled into two studies. After a total of 289 patients had been enrolled in the trial (177 in WEARIT and 112 in BIROAD), prespecified safety and effectiveness guidelines had been met. Six (75%) of eight defibrillation attempts were successful. Six inappropriate shock episodes occurred during 901 months of patient use (0.67% unnecessary shocks per month of use). Twelve deaths occurred during the study 6 sudden deaths: 5 not wearing and 1 incorrectly wearing the device). Most patients tolerated the device although 68 patients quit due to comfort issues or adverse reactions. The results of the present study suggest that a wearable defibrillator is beneficial in detecting and effectively treating ventricular tachyarrhythmias in patients at high risk for sudden death who are not clear candidates for an ICD and may be useful as a bridge to transplantation or ICD in some patients.

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

Abstract: Background— Tumor necrosis factor (TNF)-α plays a pathophysiological role in heart failure. Although both TNF receptor 1 (TNFR1) and 2 (TNFR2) are present in the heart, comparatively little is known about the role of TNFR2. Methods and Results— We bred TNFR1-knockout (KO) or TNFR2KO mice to transgenic (TG) mice with cardiac-specific overexpression of TNF-α and analyzed resultant progeny. Six groups of male and female mice were studied: wild type (WT) with wild receptors (WT/W), TG with wild receptors (TG/W), TG with heterozygous receptor KO (TG/R1+/− or TG/R2+/−), and TG with homozygous receptor KO (TG/R1−/− or TG/R2−/−). Both male and female TG mice displayed cardiac hypertrophy, dilation, and reduced cardiac function. Male TG mice were more severely affected than genotypically matched females and died of heart failure at a younger age. Survival, cardiac function, and remodeling of TG/R1+/− and TG/R1−/− mice were improved relative to TG/W mice in both males and females. However, the survival of female TG...

Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling.

Abstract: The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-α receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One h...

Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model.

Abstract: Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Cai2+) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor α (TNFα). Objective: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca2+ pump, enhances SR Ca2+ uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. Methods: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Cai2+ transients and contractile function of isolated cardiomyocytes. Results: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Cai2+ transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Cai2+ cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNFα stimulation. Conclusions: Enhancement of intrinsic cardiomyocyte Cai2+ cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.

Is there any future for tumor necrosis factor antagonists in chronic heart failure

Abstract: Over the past decade, a large number of studies have demonstrated that tumor necrosis factor-alpha (TNFalpha) plays an important role in the development of heart failure. Indeed, administration of TNFalpha to experimental animals and transgenic over-expression of TNFalpha replicate the heart failure phenotype. Furthermore, attenuation of the biologic activity of TNFalpha abrogates the development of heart failure in model systems. These pre-clinical studies, suggested that anti-cytokine therapy could prove beneficial in the treatment of patients with heart failure. While early studies supported this hypothesis, anti-TNF strategies have not demonstrated salutary benefits in large, multicenter randomized and placebo-controlled clinical trials in patients with symptomatic heart failure. This finding was disappointing. However, recent studies might provide clarification of this conundrum. For example, the failure to elicit beneficial effects with anti-cytokine therapy might be explained by novel pharmacogenomic or pharmacodynamic effects, the design of the Phase III clinical trials, or discordance between animal models and the human condition. Thus, appropriately designed clinical trials and newer anticytokine agents may demonstrate benefit.

Assessment of infarct size and myocardial function in mice using transesophageal echocardiography.

Abstract: Background Because transthoracic echocardiography (TTE) has significant limitations in assessing changes consequent to myocardial infarction (MI) in mice, we studied two novel methods to characterize such infarcts. Methods Large MIs were produced by proximal left coronary artery ligation, and small MIs by distal left coronary artery ligation. Serum cardiac troponin I levels were measured 24 hours postoperatively. At 2 weeks, mice underwent transesophageal echocardiography (TEE) and TTE. Infarct sizes were determined histologically. Results Surviving mice were classified according to infarct size. TEE identified all histologically proven large infarcts, and 4 of 5 small infarcts. TTE identified 4 of 5 large infarcts, but only 1 of 5 small infarcts. TEE-derived fractional area change, but not TTE-estimated left ventricular fractional shortening, was significantly different among large, small, and sham infarcts. Cardiac troponin I showed excellent correlation with infarct size and mortality. Conclusions Cardiac troponin I was found to predict infarct size and mortality, whereas TEE proved superior to TTE in determining infarct size and/or myocardial function in a murine MI model. These tools should provide more accurate assessments in preclinical studies of ischemic cardiomyopathy.

Clinical characteristics of vesnarinone.

Abstract: Congestive heart failure is a common condition with a poor prognosis. Its high rates of morbidity and mortality produce a huge societal burden. Current pharmacological treatment approaches are based on angiotensin-converting enzyme inhibitors, diuretics and digoxin, but up to 5% of patients may have refractory disease with persistent symptoms at rest. Such patients with advanced-stage disease may be candidates for treatment with the novel agent vesnarinone, a mixed phosphodiesterase inhibitor and ion-channel modifier that has modest, dose-dependent, positive inotropic activity, but minimal negative chronotropic activity.