Showing papers by "Arthur M. Feldman published in 2003"
TL;DR: For patients with heart failure caused by systolic function, the Asp298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.
Abstract: Background— Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction. Methods and Results— Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56±12 years) with systolic dysfunction (left ventricular ejection fraction ≤0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp298 variant. Event-free ...
126 citations
TL;DR: Both action potential prolongation and abnormal Ca(2+) handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.
Abstract: Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-α (TNF-α mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatati...
126 citations
TL;DR: The problems with the trial design of COMET are analyzed, and the theoretical reasons why postjunctional adrenergic receptor blockade that is in addition to beta1-receptor antagonism will likely produce only minimal or no incremental benefit in chronic heart failure are discussed.
77 citations
TL;DR: Transgenic TNF1.6 mice, which cardiac specifically overexpress tumor necrosis factor-α (TNF-α), exhibit heart failure (HF) and increased mortality, which is markedly higher in young (<20 wk) m...
Abstract: Transgenic (TG) TNF1.6 mice, which cardiac specifically overexpress tumor necrosis factor-α (TNF-α), exhibit heart failure (HF) and increased mortality, which is markedly higher in young (<20 wk) m...
65 citations
TL;DR: Although cyclophosphamide significantly suppressed the infiltration of inflammatory cells, it did not diminish the production of hydroxyl radical in TG myocardium, indicating that damaged myocytes, but not infiltratinginflammatory cells, may be the source of ROS in TG.
Abstract: Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-α develop congestive heart failure with myocardial inflammation. The purpose of this study was to investigate the ...
51 citations
Journal Article•
36 citations
TL;DR: It is important to note that the adrenergic, reactive oxygen species, and proinflammatory cytokine signaling pathways are not the only pro-apoptotic pathways active in the myocardium, nor are IL-6-related cytokine, calcineurin, and IGF-1/P13K/Akt signaling pathways the only anti-apopotic pathwaysActive in theMyocardium.
Abstract: The purpose of this review is to highlight those circulating molecules, membrane receptors, and signaling pathways that initiate, potentiate, or conversely, inhibit apoptosis within cardiomyocytes. This review focuses on pathways directly related to the failing heart and discusses the limitations of current methodologies for assessing cardiomyocellular apoptosis. It is important to note that the adrenergic, reactive oxygen species, and proinflammatory cytokine signaling pathways are not the only pro-apoptotic pathways active in the myocardium, nor are IL-6-related cytokine, calcineurin, and IGF-1/P13K/Akt signaling pathways the only anti-apoptotic pathways active in the myocardium. However, the are among the best-characterized apoptosis-mediating pathways and therefore they may serve as foundation for future studies aimed at identifying novel apoptotic regulating pathways active in cardiomyocytes. Considering the short history of studying cardiomyocellular apoptosis, a tremendous body of knowledge has been collected. Understandably, much more work remains. Tomorrow’s studies must (1) continue to examine the signaling pathways mediating cardiomyocellular apoptosis by focusing on the links to the ubiquitous apoptosis effectors, (2) use the expanding body of knowledge to develop more specific inhibitors of apoptosis, and then (3) confirm the causal relationship of cardiomyocellular apoptosis and cardiac dysfunction in physiologic models of cardiac challenge.
33 citations
TL;DR: It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.
14 citations