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Biomedical subjects

Arthur M Feldman

Publications and source records attributed to Arthur M Feldman.

At least 55 records · Page 3Linked to original sources
PubMed2003

Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure.

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 < or =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 survival was significantly poorer in patients with the Asp298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P=0.03). In subset analysis, the adverse impact of the Asp298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P=0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P=0.71). CONCLUSIONS: 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.

Adult↗
PubMed2003

Selective versus nonselective beta-blockade for heart failure therapy: are there lessons to be learned from the COMET trial?

The recently reported COMET trial found that the beta1/beta2/alpha1 receptor blocking agent carvedilol given in a relatively high beta1-receptor blocking dose regimen was superior in mortality reduction to immediate release metoprolol given in a relatively low beta1-receptor blocking dose schedule. We analyze the problems with the trial design of COMET from the standpoint of comparing 2 therapeutic agents at different positions on a common dose-response curve, and discuss 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.

Adrenergic beta-Antagonists↗
PubMed2003

The role of anticytokine therapy in heart failure: recent lessons from preclinical and clinical trials?

In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. 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.

Animals↗
PubMed2003

Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha.

Transgenic (TG) TNF1.6 mice, which cardiac specifically overexpress tumor necrosis factor-alpha (TNF-alpha), exhibit heart failure (HF) and increased mortality, which is markedly higher in young (<20 wk) males (TG-M) than females (TG-F). HF in this model may be partly caused by remodeling of the extracellular matrix and/or structure/function alterations at the single myocyte level. We studied left ventricular (LV) structure and function using echocardiography and LV myocyte morphometry, contractile function, and intracellular Ca(2+) (Ca(i)(2+)) handling using cell edge detection and fura 2 fluorescence, respectively, in 12-wk-old TG-M and TG-F mice and their wild-type (WT) littermates. TG-F mice showed LV hypertrophy without dilatation and only a small reduction of basal fractional shortening (FS) and response to isoproterenol (Iso). TG-M mice showed a large LV dilatation, higher mRNA levels of beta-myosin heavy chain and atrial natriuretic factor versus TG-F mice, reduced FS relative to both WT and TG-F mice, and minimal response to Iso. TG-F and TG-M myocytes were similarly elongated (by approximately 20%). The amplitude of Ca(i)(2+) transients and contractions and the response to Iso were comparable in WT and TG-F myocytes, whereas the time to 50% decline (TD(50%)) of the Ca(i)(2+) transient, an index of the rate of sarcoplasmic reticulum Ca(2+) uptake, was prolonged in TG-F myocytes. In TG-M myocytes, the amplitudes of Ca(i)(2+) transients and contractions were reduced, TD(50%) of the Ca(i)(2+) transient was prolonged, and the inotropic effect of Iso on Ca(i)(2+) transients was reduced approximately twofold versus WT myocytes. Protein expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 and phospholamban was unaltered in TG versus WT hearts, suggesting functional origins of impaired Ca(2+) handling in the former. These results indicate that cardiac-specific overexpression of TNF-alpha induces myocyte hypertrophy and gender-dependent alterations in Ca(i)(2+) handling and contractile function, which may at least partly account for changes in LV geometry and in vivo cardiac function in this model.

Animals↗
PubMed2003

The balance between pro-apoptotic and anti-apoptotic pathways in the failing myocardium.

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/PI3K/Akt signaling pathways the only anti-apoptotic pathways active in the myocardium. However, they 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.

Animals↗
PubMed2002

Calcium-dependent arrhythmias in transgenic mice with heart failure.

Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca(2+) in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 +/- 2 ms, n = 7, vs. 18 +/- 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca(2+)], and prolonged Ca(2+) transients (72 +/- 6 ms, n = 10, vs. 54 +/- 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus 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.

Action Potentials↗
PubMed2002

Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-alpha develop congestive heart failure with myocardial inflammation. The purpose of this study was to investigate the effects of tumor necrosis factor-alpha on reactive oxygen species (ROS) in this mouse model of cardiomyopathy. Myocardial production of hydroxyl radical detected by electron spin resonance spectroscopy was significantly increased in TG. Myocardial expression of Mn-SOD was significantly decreased in TG, whereas that of Cu,Zn-SOD was unaltered. Myocardial expression of catalase was unchanged, whereas that of glutathione peroxidase was significantly increased, in TG. Histological analysis revealed that macrophages and CD4-positive lymphocytes were increased in TG myocardium. To investigate whether these infiltrating inflammatory cells were the source of ROS, we treated TG mice with cyclophosphamide for 7 days. Although cyclophosphamide significantly suppressed the infiltration of inflammatory cells, it did not diminish the production of hydroxyl radical in TG myocardium. Damaged myocytes, but not infiltrating inflammatory cells, may be the source of ROS in TG.

Animals↗
PubMed2002

Chronic exposure to interleukin 1beta induces a delayed and reversible alteration in excitation-contraction coupling of cultured cardiomyocytes.

While proinflammatory cytokines can depress cardiac contractility, the mechanism by which this occurs remains unclear. To clarify the cellular effects of interleukin (IL)-1beta, we assessed contractility, calcium homeostasis, and gene expression in cardiomyocytes exposed to this proinflammatory cytokine. Neonatal rat cardiomyocytes were exposed to IL-1beta in the presence or absence of an inhibitor of nitric oxide (NO) synthase. Videomicroscopy was used to follow calcium transients (Fura-2 fluorescence) and amplitude of contraction, both unstimulated and after isoproterenol challenge. Gene expression was assessed by Northern and Western blot analyses. Both basal contractility (amplitude of contraction, maximum speed of contraction and relaxation) and amplitude of calcium transients were decreased, respectively, ca. 60% ( P< or =0.05) and ca. 40% ( P< or =0.05) after 3 days of IL-1beta exposure. Contractile function and amplitude of calcium transients returned to control values when cells where cultured an additional 3 days in the absence of IL-1beta. IL-1beta-treated cells had reduced responses to isoproterenol as evidenced by a lack of enhanced amplitude of contraction and a reduction in cAMP production. IL-1beta decreased the expression of genes important to the regulation of calcium homeostasis (phospholamban, sarcoplasmic reticulum calcium ATPase) at both the transcript and protein level. Alterations in contractile function did not occur through NO-mediated pathways. These results support the hypothesis that IL-1beta may play an important role in contractile dysfunction through alterations in calcium homeostasis.

Adrenergic beta-Agonists↗
PubMed2002

Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-alpha develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates beta-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dt(max) was significantly suppressed, and its beta-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved beta-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of beta-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.

Adrenergic beta-Agonists↗
PubMed2002

Reevaluating the role of phosphodiesterase inhibitors in the treatment of cardiovascular disease.

First developed for clinical use in the late 1980s, the phosphodiesterase inhibitors were found to increase the levels of the ubiquitous second messenger cyclic adenosine monophosphate and could effect changes in vascular tone, cardiac function, and other cellular events. After several early studies using high doses of phosphodiesterase inhibitors in patients with severe heart failure suggested adverse consequences, they fell out of favor. However, recent investigations of phosphodiesterase inhibitors in patients with intermittent claudication have demonstrated profound benefits. Furthermore, these agents have proven useful in prevention of cerebral infarction and coronary restenosis, and their use in the treatment of heart failure is being reevaluated. The reemergence of phosphodiesterase inhibitors can be attributed to a better understanding of dosing and drug-specific pharmacology, the use of concomitant medications, and a recognition of unique ancillary properties; however, their use still requires caution.

Cardiovascular Diseases↗
PubMed2002

Enhanced external counterpulsation: mechanism of action.

The mechanisms accounting forthe salutary benefits of enhanced external counterpulsation (EECP) remain largely unknown. Emerging data now point to three possible hypotheses to explain its efficacy. These possible explanations include enhanced diastolic flow, changes in the neurohumoral milieu, and changes in ventricular function independent of changes in cardiac load. While each of these three hypotheses may help explain the mechanism behind EECP's effects, more clinical studies are required to refine these proposed explanations.

Animals↗
PubMed2002

Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure.

BACKGROUND: Cytochrome P450 (CYP) enzymes are important mediators of drug metabolism, and activity of these enzymes is a major determinant of the duration and intensity of drug effect. Circulating plasma concentrations of pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]-alpha and interleukin [IL]-6) are elevated in patients with heart failure and these cytokines have been shown to down-regulate CYP enzyme activity. The purpose of this study was to evaluate the relationship between plasma cytokine concentrations and CYP enzyme activities in patients with heart failure. METHODS AND RESULTS: Sixteen patients with congestive heart failure (New York Heart Association classes II-IV) received a metabolic probe cocktail consisting of caffeine, mephenytoin, dextromethorphan, and chlorzoxazone to assess the activities of the CYP enzymes 1A2, 2C19, 2D6, and 2E1. Blood and urine samples were collected for drug and metabolite determinations by high-performance liquid chromatography (HPLC); cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA). We found a striking inverse relationship between both TNF-alpha and IL-6 plasma concentrations and the activity of CYP2C19; metabolism of caffeine (CYP1A2) also had a negative association with IL-6 plasma concentrations. CONCLUSIONS: Cytokine-mediated decreases in drug metabolism may contribute to observed variability in drug response and augment the risk of adverse drug effects in CHF patients.

Adult↗
PubMed2002

MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure.

Myocardial extracellular matrix remodeling regulated by matrix metalloproteinases (MMPs) is implicated in the progression of heart failure. We hypothesized that MMP inhibition may modulate extracellular matrix remodeling and prevent the progression of heart failure. The effects of the MMP inhibitor BB-94 (also known as batimastat) on MMP expression, collagen expression, collagen deposition, collagen denaturation, and left ventricular structure and function in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor-alpha (TNF-alpha) (TNF1.6) were assessed. The results showed that BB-94 reduced the expression of collagens, increased insoluble collagen and the ratio of undenatured to total soluble collagen, and prevented myocardial hypertrophy and diastolic dysfunction in young TNF1.6 mice. Furthermore, the treatment significantly improved cumulative survival of TNF1.6 mice. However, MMP inhibition did not have salutary effects on ventricular size and function in old mice with established heart failure. The results suggest that MMP activation may play a critical role in changes of myocardial function through the remodeling of extracellular matrix, and MMP inhibition may serve as a potential therapeutic strategy for heart failure, albeit within a narrow window during the development of heart failure.

Animals↗
PubMed2002

Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-alpha develop dilated cardiomyopathy with myocardial inflammation. The purpose of this study was to investigate the role of nitric oxide (NO) in this mouse model of cardiomyopathy. Female TG and wild-type mice at the age of 10 wk were studied. The expression and activity of inducible NO synthase (iNOS) were significantly increased in the TG myocardium, whereas those of endothelial NOS were not altered. The majority of the iNOS protein was isolated in the interstitial cells. The selective iNOS inhibitor (1S,5S,6R,7R)- 7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714) was used to examine the effects of iNOS induction on myocardial contractility. Echocardiography and left ventricular pressure measurements were performed. Both fractional shortening and the maximum rate of rise of left ventricular pressure were significantly suppressed in TG mice. Although ONO-1714 did not change hemodynamic parameters or contractility at baseline, it significantly improved beta-adrenergic inotropic responsiveness in TG mice. These results indicate that induction of iNOS may play an important role in the pathogenesis of cardiac dysfunction in this mouse model of cytokine-induced cardiomyopathy.

Adrenergic beta-Agonists↗
PubMed2002

Strain-specific patterns of autonomic nervous system activity and heart failure susceptibility in mice.

Transgenic mice are widely used to study cardiac function, but strain-dependent differences in autonomic nervous system activity (ANSA) have not been explored. We compared 1) short-term pharmacological responses of cardiac rhythm in FVB vs. C57Black6/SV129 wild-type mice and 2) long-term physiological dynamics of cardiac rhythm and survival in tumor necrosis factor (TNF)-alpha transgenic mice with heart failure (TNF-alpha mice) on defined backgrounds. Ambulatory telemetry electrocardiographic recordings and response to saline, adrenergic, and cholinergic agents were examined in FVB and C57Black6/SV129 mice. In FVB mice, baseline heart rate (HR) was higher and did not change after injection of isoproterenol or atropine but decreased with propranolol. In C57Black6/SV129 mice, HR did not change with propranolol but increased with isoproterenol or atropine. Mean HR, but not indexes of HR variability, was an excellent predictor of response to autonomic agents. The proportion of surviving animals was higher in TNF-alpha mice on an FVB background than on a mixed FVB/C57Black6 background. The homeostatic states of ANSA are strain specific, which can explain the interstrain differences in mean HR, pharmacological responses, and survival of animals with congestive heart failure. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene targeting experiments.

Adrenergic alpha-Antagonists↗