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Biomedical subjects

A M Feldman

Publications and source records attributed to A M Feldman.

At least 37 records · Page 2Linked to original sources
PubMed2001

Benefit and safety of enhanced external counterpulsation in treating coronary artery disease patients with a history of congestive heart failure.

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.

Aged↗
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

Matrix metalloproteinases in the progression of heart failure: potential therapeutic implications.

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.

Animals↗
PubMed2000

Myocarditis.

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Animals↗
PubMed2000

Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy.

Myocardial fibrosis caused by maladaptive extracellular matrix (ECM) remodeling is implicated in the dysfunction of the failing heart. Matrix metalloproteinases (MMPs) regulate ECM remodeling, and are regulated by cytokines. Transgenic mice with cardiac-specific overexpression of tumor necrosis factor alpha (TNF-alpha) (TNF1.6) develop heart failure. We hypothesized that modulation of TNF-alpha and/or MMP activity might alter the myocardial ECM remodeling process and the development of heart failure. To test this hypothesis, we took advantage of the TNF1.6 mice and studied soluble and total collagens and collagen type profiling by using hydroxyproline quantification, Sircol collagen assay, Northern blot analysis, and immunohistochemistry and studied myocardial function by using echocardiography. Progressive ventricular hypertrophy and dilation in the TNF1.6 mice were accompanied by a significant increase in MMP-2 and MMP-9 activity, an increase in collagen synthesis, deposition, and denaturation, and a decrease in undenatured collagens. In young TNF1.6 mice, these changes in the ECM were associated with marked diastolic dysfunction as demonstrated by significantly reduced transmitral Doppler echocardiographic E/A wave ratio. Anti-TNF-alpha treatment with adenoviral vector expressing soluble TNF-alpha receptor type I attenuated both MMP-2 and MMP-9 activity, prevented further collagen synthesis, deposition and denaturation, and preserved myocardial diastolic function in young, but not old, TNF1.6 mice. The results suggest a critical role of TNF-alpha and MMPs in myocardial matrix remodeling and functional regulation and support the hypothesis that both TNF-alpha and MMPs may serve as potential therapeutic targets in the treatment of heart failure.

Animals↗
PubMed2000

Trastuzumab in the treatment of metastatic breast cancer : anticancer therapy versus cardiotoxicity.

Trastuzumab, a monoclonal antibody against the HER2 receptor, was recently approved for the treatment of metastatic breast cancer. However, 28% of patients receiving both an anthracycline and trastuzumab developed heart failure. Although HER2 overexpression has been associated with the development of cancer, HER2 receptors seem to be cardioprotective because they mediate the activation of important cardiac survival pathways. Because the morbidity and mortality of heart failure surpasses that of many cancers, prudent medical practice mandates that physicians learn more about the mechanisms of trastuzumab-induced cardiotoxicity and develop algorithms for assessing risk/benefit ratios before extending the use of this agent to patients with less invasive forms of breast cancer.

Antibodies, Monoclonal↗
PubMed2000

Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy.

BACKGROUND: Transgenic mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-alpha develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutralization of TNF-alpha on this model. METHODS AND RESULTS: An adenovirus encoding the 55-kDa TNF receptor-IgG fusion protein (AdTNFRI) was injected intravenously into 6-week-old transgenic mice, which resulted in high levels of TNFRI in both plasma and myocardium. AdTNFRI did not reverse cardiomegaly but abrogated myocardial inflammation. Furthermore, AdTNFRI blocked the myocardial expression of intercellular adhesion molecule-1 and downstream cytokines, including interleukin-1beta and monocyte chemotactic protein-1. Downregulation of alpha-myosin heavy chain was restored by the treatment, whereas upregulation of beta-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban was normalized by AdTNFRI. Echocardiographic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this increase was reversed by the AdTNFRI treatment. However, left ventricular wall thickening was not reversed. CONCLUSIONS: These results suggest that anti-TNF therapy may hold promise in the treatment of end-stage heart failure.

Adenoviridae↗
PubMed2000

The role of tumor necrosis factor in the pathophysiology of heart failure.

Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn's disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.

Animals↗
PubMed2000

The role of tumor necrosis factor alpha in the pathophysiology of congestive heart failure.

A variety of clinical and experimental investigations have suggested that tumor necrosis factor alpha (TNF-alpha) may play a role in the pathophysiology of heart failure. Serum levels of TNF-alpha are elevated in patients with heart failure, and both cardiac and infiltrating cells of the myocardium can produce this proinflammatory cytokine. Both cardiac myocytes and nonmyocytes also express receptors for TNF-alpha, and experimental studies on isolated cells, muscles, and transgenic models demonstrate the ability of TNF-alpha to recapitulate functional and biochemical alterations resembling that observed in human congestive heart failure. The intracellular pathways affected by TNF-alpha include production of ceramide and an alteration in calcium metabolism. Recent studies in both animal models and clinical investigations suggest that anti-TNF-alpha therapies may limit the pathophysiologic consequences of congestive heart failure.

Animals↗
PubMed2000

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

Animals↗
PubMed2000

Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies.

OBJECTIVES: This study sought to evaluate the effects of postmenopausal estrogen use on mortality in aging women with congestive heart failure (CHF). BACKGROUND: The age-related increase in CHF mortality in women may be related to a menopause-associated increased incidence of coronary artery disease. In addition to inhibiting coronary atherosclerosis, estrogen may also have protective effects on cardiac myocytes independent of the coronary vasculature. We hypothesized that estrogen use is associated with improved survival in elderly women with CHF. METHODS: Associations between survival, estrogen use and patient characteristics were assessed in 1,134 women who were at least 50 years of age, had CHF and left ventricular ejection fraction (EF) < or =30% and were enrolled in one of three clinical trials of vesnarinone. RESULTS: All-cause 12-month mortality was 15.0% among the 237 estrogen users versus 27.1% among the 897 estrogen nonusers (p = 0.004 for unadjusted comparison of survival). Similar results were observed for cardiac mortality. Regression analysis demonstrated that estrogen use was independently associated with improved survival (relative risk of mortality = 0.68, 95% confidence interval 0.48 to 0.96, p = 0.03). Advanced age, low EF, New York Heart Association class IV CHF, Caucasian race and abnormal serum creatinine, sodium, potassium and transaminase were independently associated with increased mortality. CONCLUSIONS: Estrogen use among older women with CHF is associated with decreased overall and cardiac mortality.

Aged↗
PubMed2000

Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure.

BACKGROUND: Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, are elevated in patients with congestive heart failure (CHF). Recent studies suggest that the failing human heart is a source of proinflammatory cytokines in the end-stage failing heart. However, the relevance of plasma levels to those of the myocardium remains undefined. We sought to compare cytokine expression in early and end-stage CHF, and to evaluate the correlation of tissue expression to plasma levels. METHODS: Two patient populations were studied: patients with recent-onset CHF, all with symptoms less than 6 months (n = 17, duration of symptoms 2.1 +/- 1.6 months, range of New York Heart Association (NYHA) 1 to 3), and end-stage heart-failure patients (n = 7) who underwent left-ventricular assist-device (LVAD) implantation (Duration of symptoms 47.1 +/- 28.0 months, all NYHA class 4). Plasma levels of TNF-alpha and IL-6 proteins were evaluated by an Enzyme-Linked Immuno-Sorbent Assay (ELISA), while myocardial levels of cytokine transcripts were assessed by ribonuclease (Rnase) protection assay. RESULTS: In patients with end-stage heart failure, TNF-alpha and IL-6 were increased in the plasma as well as in the myocardium (plasma: TNF-alpha = 7.7 +/- 2.3 pg/ml, IL-6 = 45.0 +/- 47.1 pg/ml; myocardium: TNF-alpha = 0.31 +/- 0.15% of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, IL-6 = 1.56 +/- 1.54% ). In contrast, despite elevated plasma levels of TNF-alpha and IL-6, the myocardium of patients with the recent onset of symptoms demonstrated minimal expression of TNF-alpha and IL-6 messenger ribonucleic acid (mRNA) (plasma: TNF-alpha = 4.3 +/- 1.7 pg/ml, IL-6 = 3.3 +/- 1.8 pg/ml; myocardium: TNF-alpha = 0.13 +/- 0. 04%, IL-6 = 0.02 +/- 0.04%). Plasma levels of TNF-alpha were significantly correlated with those in the myocardium when both populations were combined. (r = 0.69, p < 0.001). CONCLUSIONS: Cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent-onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF. Furthermore, plasma levels of TNF-alpha correlates with mRNA expression in the myocardium and thus may serve as an appropriate marker of myocardial cytokine activation. Whether the production of cytokines in the failing human heart precedes the elevation of cytokines in the plasma remains undefined. Therefore, we studied expression of TNF-alpha and IL-6 in the myocardium as well as in the plasma in patients with early and end-stage CHF. The results have demonstrated that cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF.

Adult↗
PubMed2000

Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators.

BACKGROUND: Although pharmacological therapy has ameliorated symptoms and improved the survival of patients with chronic heart failure (CHF), this chronic syndrome remains a progressive disease causing incremental morbidity and early mortality. A new therapy for the treatment of CHF should ideally decrease mortality, alleviate symptoms, and improve functional capacity. A growing body of evidence suggests that the use of implantable devices to resynchronize ventricular contraction may be a beneficial adjunct in the treatment of CHF. METHODS: The Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial is a randomized, open-label, 3-arm study of patients in New York Heart Association class III or IV with an ejection fraction of 35% or less and a QRS duration of 120 milliseconds or less. The COMPANION study objectives are to determine whether optimal pharmacological therapy used with (1) ventricular resynchronization therapy alone or (2) ventricular resynchronization therapy combined with cardioverter-defibrillator capability is superior to optimal pharmacological therapy alone in reducing combined all-cause mortality and hospitalizations; reducing cardiac morbidity; improving functional capacity, cardiac performance, and quality of life; and increasing total survival.

Cardiovascular Agents↗
PubMed2000

Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression.

Epidemiological evidence suggests that the prognosis of heart failure in women is better than in men. In our murine model of dilated cardiomyopathy arising from cardiac-specific overexpression of TNF-alpha, the 6-month survival rate was significantly better in females than in males. Young female transgenic mice exhibited left ventricular wall thickening without dilatation, whereas age-matched male transgenic hearts were markedly dilated. Basal and isoproterenol-stimulated fractional shortening was preserved in female transgenic mice, but not in male transgenic mice. Myocardial expression of proinflammatory cytokines and the extent of myocardial infiltrates were similar in male and female transgenic mice. Myocardial expression of TNF-receptor mRNAs (type I and type II) was significantly higher in male mice in both transgenic and wild-type littermates, whereas sex-specific differences were not observed in either peripheral white blood cells or liver tissue. After TNF-alpha challenge, myocardial but not liver production of ceramide was significantly higher in male than in female mice. Thus, differential expression of myocardial TNF receptors may contribute to sex differences in the severity of congestive heart failure and mortality consequent to cardiac-specific overexpression of TNF-alpha.

Animals↗
PubMed2000

From clinical trials to clinical practice: what we know and do not know about beta-blockers and the heart.

In the early 1980s, several lines of evidence suggested the possibility that decreasing adrenergic drive could be beneficial in patients with chronic heart failure. Clinical trials conducted in the 1990s have unequivocally shown that beta-blockade improves left-ventricular ejection fraction (LVEF) in the failing heart. Beta-blockers represent the only medical treatment that has been shown to reverse the pathological myocardial remodeling observed in patients with chronic heart failure. Beta-blockers are now a mainstay of therapy for patients with New York Heart Association (NYHA) class II and III heart disease; however, several issues remain unresolved regarding beta-blocker treatment of heart failure, including (1) the potential role of beta-blockers in asymptomatic (NYHA class I) patients; (2) the potential role of beta-blockers in patients with severe (NYHA class IV) heart failure; (3) the possibility of more rapid dose titration; and (4) the influences of sex, age, and race. Further studies evaluating the efficacy of beta-blockade in class I and class IV patients are forthcoming; the results of these trials will help to determine the role of beta-blocker therapy in patients at the extremes of heart failure (ie, asymptomatic patients and those with advanced heart failure). This article discusses the issues that still remain regarding the transitioning of beta-blockade from clinical trials to clinical practice and indicates areas in which further research is warranted. Finally, barriers to treatment are discussed as well as possible strategies for overcoming these obstacles.

Adrenergic beta-Antagonists↗