Showing papers by "Arthur M. Feldman published in 2001"
TL;DR: The American College of Cardiology (ACC) and the American Heart Association (AHA) first published guidelines for the evaluation and management of heart failure (HF) in 1995, and since that time, a great deal of progress has been made in the development of both pharmacological and nonpharmacological approaches to treatment for this common, costly, disabling, and generally fatal disorder.
1,829 citations
TL;DR: In the United States, nearly 5 million patients in this country have heart failure, and nearly 500,000 patients are diagnosed with heart failure for the first time each year as mentioned in this paper.
Abstract: References......2112
Heart failure (HF) is a major public health problem in the United States. Nearly 5 million patients in this country have HF, and nearly 500,000 patients are diagnosed with HF for the first time each year. The disorder is the underlying reason for 12 to 15 million office visits
1,222 citations
TL;DR: In this paper, the authors 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.
Abstract: 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 mo...
922 citations
TL;DR: It is suggested that for patients with recent-onset dilated cardiomyopathy, IVIG does not augment the improvement in LVEF, however, in this overall cohort, LVEf improved significantly during follow-up, and the short-term prognosis remains favorable.
Abstract: Background—This prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis Methods and Results—Sixty-two patients (37 men, 25 women; mean age ±SD 430±123 years) with recent onset (≤6 months of symptoms) of dilated cardiomyopathy and LVEF ≤040 were randomized to 2 g/kg IVIG or placebo All underwent an endomyocardial biopsy before randomization, which revealed cellular inflammation in 16% The primary outcome was change in LVEF at 6 and 12 months after randomiz Overall, LVEF improved from 025±008 to 041±017 at 6 months (P<0001) and 042±014 (P<0001 versus baseline) at 12 months The increase was virtually identical in patients receiving IVIG and those given placebo (6 months: IVIG 014±012, placebo 014±014; 12 months: IVIG 016±012, placebo 015±016) Overall, 31 (56%) of 55 patients at 1 year had an increase in LV
499 citations
TL;DR: Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.
Abstract: Background —Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known. Methods and Results —We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m 2 (n=16) or 12 mg/m 2 (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m 2 etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score. Conclusion —Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.
368 citations
TL;DR: The reduced MMPs and increased TIMPs and ratios of undenatured to total soluble collagens and insoluble to total insolubleCollagens after LVAD support suggest that reduced M MP activity diminished damage to the matrix.
Abstract: Background— Left ventricular assist device (LVAD) support of the failing heart induces salutary changes in myocardial structure and function. Matrix metalloproteinases (MMPs) are increased in the failing heart and are induced by stretch in cardiac cells in vitro. We hypothesized that mechanical unloading may affect LV plasticity by regulating MMPs and their substrates. Methods and Results— LV samples were collected from patients with dilated cardiomyopathy (DCM, n=14) or ischemic cardiomyopathy (ICM, n=16) at the time of implantation of the LVAD and again during cardiac transplantation. MMP-1, -3, and -9 were measured by ELISA, MMP-2 and -9 gelatinolytic activity by gelatin zymography, and tissue inhibitors of metalloproteinases (TIMPs) by Western blot. Total soluble and insoluble collagens were separated by pepsin solubilization, and the contents were determined by quantification of hydroxyproline. The undenatured soluble collagen was measured by Sircol collagen assay. The results showed that MMP-1 and -...
273 citations
TL;DR: In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival, suggesting a potential pharmacogenetic interaction between theACE D/I polymorphism and therapy with β-blockers in the determination of heart failure survival.
Abstract: Background —Activation of the renin-angiotensin and sympathetic nervous systems adversely affect heart failure progression. The ACE deletion allele ( ACE D ) is associated with increased renin-angiotensin activation; however, its influence on patient outcomes remains uncertain, and the pharmacogenetic interactions with β-blocker therapy have not been previously evaluated. Methods and Results —We prospectively followed 328 patients (age, 56.1±11.9 years) with systolic dysfunction (left ventricular ejection fraction, 0.24±0.08) to assess the impact of the ACE D allele on transplant-free survival (median follow-up, 21 months). Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n=120) and those without β-blocker therapy (n=208) at the time of entry. Transplant-free survival was significantly poorer for patients with the D allele (1-year percent survival II/ID/DD =94/77/75; 2-year=78/65/60; ordered log-rank test, P =0.044). In patients not treated with β-blockers, the adverse impact of ACE D allele was dramatically increased (1-year percent survival II/ID/DD =95/75/67; 2-year=81/61/48; P =0.005). In contrast, in patients receiving β-blocker therapy, no influence of ACE genotype on transplant-free survival was evident (1-year percent survival II/ID/DD =91/80/86; 2-year=70/71/77; P =0.73). Conclusions —In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival. This effect was primarily evident in patients not treated with β-blockers and was not seen in patients receiving therapy. These findings suggest a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with β-blockers in the determination of heart failure survival.
190 citations
TL;DR: The results suggest that TNF- α by itself is not sufficient to induce apoptosis in cardiac myocytes in vivo, and signaling pathways responsible for T NF-α induced apoptosis should be elucidated.
114 citations
TL;DR: The Registry population comprises all patients starting EECP therapy for treatment of angina pectoris in participating centers, and it is concluded that the number of patients in the Registry is likely to increase over the course of the treatment period.
Abstract: Summary Background: In 1998, the International EECP Patient Registry (IEPR) was organized to document patient characteristics, safety, and efficacy during the treatment period, and long-term outcomes. All centers with EECP facilities were invited to join the voluntary Registry. The Registry population comprises all patients starting EECP therapy for treatment of angina pectoris in participating centers. Hypothesis: The study was undertaken to determine whether EECP is a safe and effective treatment for patients with angina pectoris regardless of their suitability for revascularization by more conventional techniques. Methods:After 18 months of operation, 43 clinical centers representing over half of clinical sites using the EECP system contributed cases. The data reported here were collected before the first EECP treatment and upon completion of final treatment. EECP can be used for patients ineligible for either coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), as well as for those who prefer noninvasive treatment to avoid or delay revascularization. In this report, patients considered to be candidates for revascularization are compared with those not considered suitable. Results: Of the 978 patients analyzed, 70% had Canadian Cardiovascular Society Classification class III or IV angina before starting treatment, and 62% used nitroglycerin. Most (81%) had been previously revascularized, and 69% were considered unsuited for either PCI or CABG at the time of starting EECP. A full treatment course (usually 35 h) was completed in 86%, of whom 81% reported improvement of at least one angina class immediately after the last treatment. Conclusion:In a broad patient population, EECP has been shown to be a safe and effective treatment.
107 citations
TL;DR: Blockade of TNF-&agr; bioactivity by antibody therapy may both preserve cardiac function and partially reverse pathological changes in congestive heart failure.
Abstract: Background— Tumor necrosis factor (TNF)-α has been implicated in the pathophysiology of congestive heart failure. A strain of transgenic mice (TNF1.6) with cardiac-specific overexpression of TNF-α develop congestive heart failure. Methods and Results— To determine the effect of anti-TNF-α therapy in this model, we studied 3 groups: TNF1.6 mice treated with saline, wild-type mice treated with saline, and TNF1.6 mice treated with TNF-α neutralizing antibody (cV1q) from 6 to 12 weeks of age. We used echocardiography to compare cardiac hypertrophy, function, and catecholamine response at 12 weeks of age versus baseline (6 weeks). cV1q treatment did not limit cardiac hypertrophy, but it significantly improved basal fractional shortening and responsiveness to β-adrenergic stimulation, and it limited development of cardiac dilation. Conclusions— Blockade of TNF-α bioactivity by antibody therapy may both preserve cardiac function and partially reverse pathological changes in congestive heart failure.
106 citations
TL;DR: Cardiac mtDNA repair mechanisms, mtDNA damage, and mitochondrial structure and function in mice with heart failure secondary to overexpression of TNF-&agr; (TNF1.6 mice) are studied to suggest that mtDNA mutations and mitochondrial structural and functional alterations in TNF–induced heart failure may be associated with reduced mt DNA repair activity.
Abstract: Background Recent studies suggest that mutations in cardiac mitochondrial DNA (mtDNA) may contribute to the development of dilated cardiomyopathy. The mechanisms that regulate those mutations, however, remain undefined. Thus, we studied cardiac mtDNA repair mechanisms, mtDNA damage, and mitochondrial structure and function in mice with heart failure secondary to overexpression of TNF-α (TNF1.6 mice). Methods and Results We studied mtDNA repair by measuring the uracil DNA glycosylase (mtUDG) and base excision repair activities. mtDNA damage was assessed by Southern blot of Fpg protein–digested mtDNA. Mitochondrial ultrastructural changes were examined by electron microscopy, and function by cytochrome c oxidase and succinate dehydrogenase activity assays. The results showed that both mtUDG and base excision repair activities were significantly reduced in TNF1.6 mouse heart. Fpg-sensitive sites were markedly increased in TNF1.6 mouse cardiac mtDNA, suggesting increased mtDNA damage. Mitochondrial function a...
TL;DR: Inability to block myocardial expression of IL-6 and MCP-1 suggests a possible mechanism for the failure of anti-TNF therapies in the treatment of endotoxin shock, and differentially altered the cytokine expression in the plasma and myocardium during endotoxemia.
Abstract: Tumor necrosis factor (TNF)-α plays a key role in the pathogenesis of septic shock syndrome, and myocardial TNF-α expression may contribute to this pathophysiology. We examined the myocardial expre...
TL;DR: This research was supported by a grant from the National Science Foundation and the US Department of Energy's Office of Science and Technology Policy.
Abstract: ROBERT C. BOURGE, MD, FACC ANNETINE GELIJNS, PhD BARTLEY P. GRIFFITH, MD RAY E. HERSHBERGER, MD, FACC SHARON HUNT, MD, FACC JAMES KIRKLIN, MD, FACC LESLIE W. MILLER, MD, FACC WALTER E. PAE, JR., MD, FACC GEORGE PANTALOS, PhD D. GLENN PENNINGTON, MD, FACC ERIC A. ROSE, MD, FACC JOHN T. WATSON, PhD
TL;DR: Results suggest that modulation of MMP activity can prevent myocardial dysfunction and the progression of heart failure through alterations in the remodelling process of extracellular matrix and the left ventricle.
Abstract: Matrix metalloproteinases (MMPs) are a family of functionally related zinc-containing enzymes that denature and degrade fibrillar collagens and other components of the extracellular matrix. Myocardial extracellular matrix remodelling and fibrosis regulated by MMPs are believed to be important contributors to the progression of heart failure. The role of MMPs in cardiac fibrosis and the progression of heart failure, along with the possibility of halting the progression of heart failure by modulating extracellular matrix remodelling are important issues under intense study. MMPs are increased in the failing hearts of both animal models and patients with heart failure. MMP inhibition may therefore modulate extracellular matrix remodelling and the progression of heart failure. It is a great advantage that various MMP inhibitors have been developed initially for the treatment of cancer, arthritis and other diseases believed to be associated with increased MMP activity. Several preclinical studies have shown that treatment of heart failure in animal models with MMP inhibitors results in less collagen matrix damage, favourable extracellular matrix remodelling, and improved cardiac structure and function. The results suggest that modulation of MMP activity can prevent myocardial dysfunction and the progression of heart failure through alterations in the remodelling process of extracellular matrix and the left ventricle. Although these promising results suggest potential benefits of MMP inhibition for human heart failure, no clinical data evaluating MMP inhibitors in heart failure have been reported. As the preclinical evidence continues to grow and the potential of MMP inhibition for the treatment of heart failure continues to unfold, MMP inhibition may prove to be an effective treatment for heart failure.
TL;DR: Patients with congestive heart failure maintained their reduction in angina but were significantly more likely to have experienced a MACE end point at 6 months, while the angina class improved in 68%, with comparable quality of life benefit, in the heart failure cohort.
Abstract: Enhanced external counterpulsation (EECP) is used to noninvasively treat refractory angina patients, including those with a history of heart failure. The International EECP Patient Registry was used to examine the benefit and safety of EECP treatment, including a 6-month follow-up, in 1,957 patients, 548 with a history of heart failure. The heart failure cohort was older, with more females, a greater duration of coronary artery disease, more prior infarcts and revascularizations. Significantly fewer heart failure patients completed the course of EECP, and exacerbation of heart failure was more frequent, though overall major adverse cardiac events (MACE, i.e. death, myocardial infarction, revascularization) during treatment were not significantly different. The angina class improved in 68%, with comparable quality of life benefit, in the heart failure cohort. At 6 months, patients with congestive heart failure maintained their reduction in angina but were significantly more likely to have experienced a MACE end point.
TL;DR: 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.
TL;DR: The purpose of this study was to describe the pharmacokinetics of etanercept in patients with heart failure, and found that the drug was generally well tolerated in the patients studied and its pharmacokinetic parameters were generally well understood.
Abstract: Although the cause of disease progression is multifactorial, recent studies have demonstrated that the development of symptomatic heart failure is associated with an increase in circulating levels of the proinflammatory cytokine tumour necrosis factor (TNF) [1, 2]. Thus, investigators proposed that inhibition of TNF expression or bioavailability might have salutory effects in patients with symptomatic heart failure.
Etanercept (TNFR : Fc, Enbrel®) is a recombinant, human, fusion protein that binds to TNF, prohibiting its proinflammatory action. After subcutaneous administration, its pharmacokinetic parameters have been characterized in healthy volunteers and patients with rheumatoid arthritis [3, 4]. It is slowly absorbed (tmax=51–72 h) and slowly cleared (CL/F = 0.089–0.137 l h−1; t½ = 68–115 h). Because of its large molecular size etanercept may be eliminated by the reticuloendothelial system of the liver or spleen [3]. Etanercept is presently undergoing evaluation as a therapeutic option for patients with heart failure in two clinical trials; one in the US (RENAISSANCE) and a second in Europe, Australia and New Zealand (RECOVER).
Heart failure can affect the pharmacokinetic characteristics of many medications, although unfortunately, not in a predictable manner [5, 6]. The purpose of this study was to describe the pharmacokinetics of etanercept in patients with heart failure.
Eleven patients, nine males and two females, with NYHA class II–IV heart failure participated in this open-label pharmacokinetic portion of a larger study after completing a double-blind, randomized multiple-dose safety trial [7]. Their ages ranged from 31 to 74 years. Mean creatinine clearance was 99 ml min−1 (range 48–134 ml min−1). Concomitant medications had been stable for at least 1 month prior to randomization.
Patients had received a dose of 12 mg m−2 (maximum dose 25 mg) of etanercept (Enbrel, Immunex Corporation) by subcutaneous injection twice weekly for 12 weeks. Twice-weekly dosing necessitated uneven dosage intervals of 72 h and 96 h. Care was taken that all patients be studied during a 96 h dosing interval. Serial serum samples were collected by separate venipuncture before and at 2, 4, 12, 24, 36, 48, 60, 72, and 96 h after drug administration. Each sample was immediately centrifuged in the cold and the supernatant removed and frozen.
Etanercept serum concentrations were measured using an ELISA method with a limit of quantification of 0.3 ng ml−1. The coefficient of variation for the quality controls was less than 7%. Adequate storage stability had been previously demonstrated.
The serum concentration data were analysed using a noncompartmental method [8]. The maximum serum concentration (Cmax) and tmax were determined directly from the observed concentration data. The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal rule. Apparent clearance after oral administration (CL/F) was calculated as a ratio of dosing rate to AUC. Summary statistics were calculated for concentration and for Cmax, tmax, AUC, and CL/F for all patients.
Pharmacokinetic parameters for etanercept are shown in Table 1. Concentrations measured prior to dose administration (Co) are also reported.
Table 1
Multiple-dose etanercept pharmacokinetic parameters in heart failure patients.
Etanercept was generally well tolerated in the patients studied [7]. Mild, injection-site reactions were the primary adverse events related to study drug administration. These occurred in 10% of patients treated with etanercept on at least one occasion, and disappeared after the first month.
This publication provides the first pharmacokinetic data for etanercept in patients with heart failure. The very small number of patients studied limit this report to a preliminary estimate of true parameter values, but the CL/F values reported here are similar to those reported for healthy volunteers and patients with rheumatoid arthritis after single doses.
TL;DR: The results suggest that the two forms of ephrin-A5 share similar function while differ in regulating different sets of genes in cardiomyocytes.
Abstract: Eph receptors constitute the largest family of receptor tyrosine kinases. Multiple transcripts of ephrin-A5, the cognate ligand of the EphA3 receptor, were found in neonatal rat cardiomyocytes. Two cDNA clones encoding the full-length ephrin-A5 (ephrin-A5α) and a 27-amino acid deletion form (ephrin-A5β) were isolated. To examine the role of ephrin-A5 in cardiomyocytes, the cDNAs were inserted into adenoviral vectors, termed Ad.ephrin-A5α and Ad.ephrin-A5β, respectively, and overexpressed in cardiomyocytes. The effect of ephrin-A5 on cardiomyocyte gene expression was investigated using a cDNA expression array and Western blot analysis. The results showed that both ephrin-A5α and ephrin-A5β downregulated cyclin D2, cyclin-dependent kinase-4 proteins, and their cognate receptor EphA3, which were associated with reduced bromodeoxyuridine incorporation in cardiomyocytes. Whereas ephrin-A5α and ephrin-A5β also induced differential gene expression, only ephrin-A5β significantly upregulated the transcription of brain natriuretic peptide and downregulated ras-related protein RAB2, protein kinase C inhibitor protein-1, clusterin, and insulin-like growth factor-binding protein. The results suggest that the two forms of ephrin-A5 share similar function while differ in regulating different sets of genes in cardiomyocytes.
TL;DR: The hypothesize that the toxic radical peroxynitrite, arising from nitric oxide and superoxide anion, may be responsible for tetany and acute cardiomyocyte death and demonstrate the potential role of peroxyspine in cardiotoxicity.
01 Jan 2001
TL;DR: This Chapter will review in detail the observations from animal models that have supported the “Cytokine Hypothesis” of heart failure and will detail how animal models of cytokine over-expression have provided novel experimental platforms for evaluating the efficacy of anti-cytokines pharmacotherapy.
Abstract: Heart failure secondary to systolic dysfunction is a progressive cardiovascular disease that affects over 5 million people in the U.S. While the initial cause of heart failure in most patients is myocardial damage, the heart usually accommodates to the damage. However, over time, the heart remodels with the development of cardiac dilatation, cellular hypertrophy, cell slippage, diminished adrenergic responsiveness, apoptosis and extracellular matrix fibrosis and restructuring. Over the past decade, there has been a substantive increase in our knowledge of the pathobiology of the development of the heart failure phenotype. This increased knowledge has in part been attributable to advances in the sciences of cell and molecular biology and their application to studies of the failing human heart. However, our improved understanding of the molecular and cellular events leading to the development of heart failure and in particular the transition from compensated to de-compensated myocardial function can also be attributed to studies of new and novel animal models. Indeed, it is studies in animal models that have contributed seminal information regarding the fundamental role of the pro-inflammatory cytokines in the development of the heart failure phenotype. This Chapter will review in detail the observations from animal models that have supported the “Cytokine Hypothesis” of heart failure and will detail how animal models of cytokine over-expression have provided novel experimental platforms for evaluating the efficacy of anti-cytokine pharmacotherapy.