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Biomedical subjects

J Lindenfeld

Publications and source records attributed to J Lindenfeld.

At least 19 recordsLinked to original sources
PubMed2004

Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

BACKGROUND: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. METHODS AND RESULTS: Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. CONCLUSIONS: In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Adrenergic beta-Antagonists↗
PubMed2001

Aspirin impairs reverse myocardial remodeling in patients with heart failure treated with beta-blockers.

OBJECTIVES: We hypothesized that aspirin (ASA) might alter the beneficial effect of beta-blockers on left ventricular ejection fraction (LVEF) in patients with chronic heart failure. BACKGROUND: Aspirin blunts the vasodilation caused by both angiotensin-converting enzyme (ACE) inhibitors and beta-blockers in hypertensive patients and in patients with heart failure. Several studies suggest that ASA also blunts some of beneficial effects of ACE inhibitors on mortality in patients with heart failure. To our knowledge, there have been no data evaluating the possible interaction of ASA and beta-blockers on left ventricular remodeling in patients with heart failure. METHODS: We retrospectively evaluated patients entered into the Multicenter Oral Carvedilol Heart failure Assessment (MOCHA) trial, a 6-month, double-blind, randomized, placebo-controlled, multicenter, dose-response evaluation of carvedilol in patients with chronic stable symptomatic heart failure. Multivariate analysis was performed to determine if aspirin independently influenced the improvement in LVEF. RESULTS: Over all randomized patients (n = 293), LVEF improved 8.2 +/- 0.8 ejection fraction (EF) units in ASA nonusers and 4.5 +/- 0.7 EF units in ASA users (p = 0.005). In subjects randomized to treatment with carvedilol (n = 231), LVEF improved 9.5 +/- 0.9 EF units in ASA nonusers and 5.8 +/- 0.8 EF units in ASA users (p = 0.02). In subjects randomized to treatment with placebo (n = 62), LVEF improved 2.8 +/- 1.2 EF units in ASA nonusers and 0.5 +/- 1.4 EF units in ASA users (p = 0.20). Aspirin did not significantly affect the heart rate or systolic blood pressure response in either the placebo or carvedilol groups. The effect of ASA became more significant on multivariate analysis. The change in LVEF was also influenced by carvedilol dose, etiology of heart failure, baseline heart rate, EF and coumadin use. The detrimental effect of ASA on the improvement in LVEF was dose-related and was present in both placebo and carvedilol groups, although the effect was statistically significant only in the much larger carvedilol group. CONCLUSIONS: Aspirin significantly affects the changes in LVEF over time in patients with heart failure and systolic dysfunction treated with carvedilol. The specific mechanism(s) underlying this interaction are unknown and further studies are needed to provide additional understanding of the molecular basis of factors influencing reverse remodeling in patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed2001

An institution-specific heparin titration nomogram: development, validation, and assessment of compliance.

STUDY OBJECTIVE: To develop, validate, and assess compliance with a heparin titration nomogram. DESIGN: Prospective, open-label trial. SETTING: University teaching hospital. SUBJECTS: Patients admitted with heart failure who required therapy with intravenous unfractionated heparin. Intervention. An in vitro concentration-response was determined by measuring activated partial thromboplastin times (aPTTs) on normal pooled plasma containing known concentrations of heparin. The therapeutic aPTT range was determined from the concentration-response by using the therapeutic heparin concentration range of 0.2-0.4 U/ml (protamine neutralization). Patients were consecutively enrolled, and therapy was managed by using the heparin titration nomogram. Paired aPTT-heparin concentrations were obtained, and nomogram validation was performed by comparing the in vitro and the ex vivo concentration-responses with use of linear regression. Nomogram compliance also was assessed. MEASUREMENTS AND MAIN RESULTS: The therapeutic aPTT ranges based on in vitro and ex vivo data were determined to be 45-72 seconds and 47-61 seconds, respectively. The ranges were significantly different (p<0.001). Overall compliance with the nomogram was 88%. CONCLUSION: These results confirm that, even in a relatively homogeneous disease-state patient population, in vitro data do not accurately predict ex vivo data. If in vitro data are used to develop an institution-specific nomogram, a validation procedure should be used to ensure accuracy. Although 100% compliance to a nomogram may not be attainable, it should be expected. Therefore, a compliance rate of 88% is concerning and suggests a need for increased nursing and physician education.

Anticoagulants↗
PubMed2000

Identification of risk factors for increased cost, charges, and length of stay for cardiac patients.

BACKGROUND: In this study we explored different risk model options to provide clinicians with predictions for resource utilization. The hypotheses were that predictors of mortality are not predictive of resource consumption, and that there is a correlation between cost estimates derived using a cost-to-charge ratio or a product-line costing approach. METHODS: From March 1992 to June 1995, 2,481 University of Colorado Hospital patients admitted for ischemic heart disease were classified by diagnosis-related group code as having undergone or experienced coronary bypass procedures (CBP), percutaneous cardiovascular procedures (PCVP), acute myocardial infarction (AMI), and other cardiac-related discharges (Other). For each diagnosis-related group, Cox proportional hazards models were developed to determine predictors of cost, charges, and length of stay. RESULTS: The diagnosis groups differed in the clinical factors that predicted resource use. As the two costing methods were highly correlated, either approach may be used to assess relative resource consumption provided costs are reconciled to audited financial statements. CONCLUSIONS: To develop valid prediction models for costs of care, the clinical risk factors that are traditionally used to predict risk-adjusted mortality may need to be expanded.

Aged↗
PubMed2000

Beta-blockade in adriamycin-induced cardiomyopathy.

Beta-blockade consistently improves myocardial systolic function in patients with both nonischemic and ischemic cardiomyopathy. The effects of beta-blockade on Adriamycin-induced cardiomyopathy (ACM), however, are unknown. We retrospectively evaluated the effects of beta-blockade on patients with ACM by using a case-controlled design. The control group consisted of 16 consecutively chosen age- and sex-matched patients with idiopathic dilated cardiomyopathy (IDC) who were treated with beta-blockers. Patients with ACM had a baseline mean left ventricular ejection fraction (LVEF) of 28%, which improved to 41% (P = .041) after treatment with beta-blockers. The control group had a baseline mean LVEF of 26%, which improved to 32% (P = .015) after treatment. The mean duration of beta-blocker therapy in the Adriamycin and control groups was 8 and 9 months, respectively. The degree of improvement between the 2 groups was not significantly different. Beta-blockers have a beneficial effect on cardiac function in patients with ACM, which is at least comparable with other forms of heart failure with systolic dysfunction.

Adrenergic beta-Antagonists↗
PubMed1999

Hypotension with dobutamine: beta-adrenergic antagonist selectivity at low doses of carvedilol.

OBJECTIVE: To report a case of marked hypotension resulting from the concomitant use of low-dose carvedilol and intravenous dobutamine. CASE SUMMARY: A 54-year-old white man with severe heart failure was placed on carvedilol 3.125 mg orally twice a day; three days later the dosage was increased to 6.25 mg orally twice a day. His symptoms of heart failure worsened with increasing fluid retention, orthopnea, paroxysmal nocturnal dyspnea, and elevated blood urea nitrogen and creatinine. He was admitted for treatment of decompensated heart failure with intravenous dobutamine. With each increase in intravenous dobutamine, systolic blood pressure fell. Dobutamine was discontinued when systolic blood pressure reached 56 mm Hg. In a subsequent admission for decompensated heart failure, when the patient was not taking carvedilol, he was treated with intravenous dobutamine and systolic blood pressure increased. DISCUSSION: Although carvedilol is a nonselective beta-adrenergic antagonist, at low doses it is a selective beta1-adrenergic antagonist. Dobutamine is a beta1-, beta2-, and alpha1-adrenergic agonist. Typically, patients with heart failure treated with intravenous dobutamine have a small increase in systolic blood pressure. We propose that the drop in blood pressure with dobutamine in this patient was caused by a fall in systemic vascular resistance due to vascular beta2-adrenergic receptor activation. The normal increase in cardiac output was partially blocked by selective beta1-adrenergic blockade at low doses of carvedilol. CONCLUSIONS: Beta-adrenergic blockade with carvedilol is now common therapy for patients with congestive heart failure. Intravenous dobutamine is often used when these patients have worsening heart failure. Recognition that treatment with dobutamine in patients taking low doses of carvedilol may result in hypotension is important for appropriate monitoring and therapy.

Adrenergic beta-Agonists↗
PubMed1997

Where are all the women with heart failure?

In recent clinical trials of medical therapy for heart failure, only approximately 20% of patients enrolled were women. The reasons for the low enrollment of women have not been clear. Although the incidence of heart failure is higher in men than in women, the prevalence is equal. When men and women with heart failure and a low left ventricular ejection fraction are compared, the women are more symptomatic and have a similarly poor outcome. Because mortality is worse in men than in women in large populations of patients with heart failure, there may be important pathophysiologic differences. Substantial data suggest that women may have diastolic dysfunction more often than men. This difference would explain differences in mortality and the difficulty in enrolling women in studies of medical therapy for heart failure with underlying systolic dysfunction.

Diastole↗
PubMed1997

Tissue plasminogen activator (tPA) inhibits human neutrophil superoxide anion production in vitro.

Because neutrophils contribute to reperfusion injury associated with acute myocardial infarction (MI), and because tissue plasminogen activator (tPA) is often used in the management of MI, we evaluated the effect of tPA on superoxide (O2.-) production by human neutrophils in vitro. We found that adding increasing amounts of tPA significantly (r = 0.89, P < 0.025) and progressively reduced O2.- generation by neutrophils treated with phorbol myristate acetate (PMA) in vitro. Furthermore, adding tPA that had been previously treated with the protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone HCl (PPACK), also decreased neutrophil O2.- generation in vitro (P < 0.05). In contrast, adding L-arginine, a component of the tPA preparation and a precursor of nitric oxide (NO), did not inhibit PMA-induced neutrophil O2.- production. Also, adding increasing concentrations of tPA did not reduce (P > 0.05) the concentrations of O2.- produced by xanthine oxidase (XO) in vitro. Our findings suggest that tPA reduces neutrophil O2.- generation by a mechanism that is not related to L-arginine, is not dependent on tPA proteolytic activity, and is not a function of direct scavenging. This property may account for some of the effectiveness of tPA in the treatment of MI and/or make tPA valuable for treating acute respiratory distress syndrome (ARDS) or other inflammatory disorders involving neutrophil O2.- production.

Amino Acid Chloromethyl Ketones↗
PubMed1995

Cardiac beta-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury. Evidence for catecholamine-mediated myocardial damage.

BACKGROUND: Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the beta-receptor-G-protein-adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results with 13 age-matched nonfailing (NF) organ donor controls. METHODS AND RESULTS: As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16 +/- 2%, mean +/- SEM). Although total and subpopulation beta-receptor densities measured by [125I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211 +/- 25 [DHD] versus 295 +/- 23 [NF] pmol cAMP.min-1.mg-1, P < .05) and 5'-guanylylimidodiphosphate (12.5 +/- 1.8 [DHD] versus 19.6 +/- 3.2 [NF] pmol cAMP.min-1.mg-1, P < .05), but there was no significant decrease in adenylyl cyclase stimulation by Mn2+, a direct activator of adenylyl cyclase. Right ventricular trabeculae removed from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7 +/- 1 [DHD] versus 22 +/- 2 [NF] mN, P < .001) as well as reduced calcium responses (7.2 +/- 1.6 [DHD] versus 14 +/- 3 [NF] mN, P = .03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity between the two groups. CONCLUSIONS: Compared with NF hearts, DHD hearts exhibit marked uncoupling of beta 1- and beta 2-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in beta-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.

Adenylyl Cyclases↗
PubMed1995

Cardiac allograft failure: successful use of biventricular assist device.

Nonspecific primary allograft dysfunction is an important cause of perioperative death in cardiac transplant recipients. We report a case of severe nonspecific allograft dysfunction that was ultimately reversible after 18 days of biventricular mechanical circulatory support. Allograft recovery was echocardiographically recognized by a positive inotropic response to isoproterenol and milrinone. This case illustrates the potential for recovery of even extreme allograft dysfunction.

Adult↗
PubMed1994

Comparative hemodynamic effects of OPC-18790 and dobutamine in patients with advanced heart failure.

OPC-18790 (Otsuka America Pharmaceutical, Rockville, MD), a novel positive inotropic agent, produces titratable hemodynamic benefits in patients with advanced heart failure. In such patients, OPC-18790 has been shown to acutely increase the cardiac index, while reducing systemic vascular resistance and left ventricular filling pressure, without an associated increase in heart rate. This study was performed to compare the acute hemodynamic effects of OPC-18790 and the beta-adrenergic receptor agonist, dobutamine, in patients with advanced heart failure. OPC-18790 and dobutamine were compared on successive days in 13 patients with worsening New York Heart Association class III or IV heart failure. The mean (+/- SEM) left ventricular ejection fraction was 15 +/- 2% (range, 6-29%). Pretreatment hemodynamics were: heart rate, 96 +/- 2 beats/min; mean arterial pressure, 77 +/- 3 mmHg; cardiac index, 1.80 +/- 0.10 L/min/m2; pulmonary capillary wedge pressure, 27 +/- 1 mmHg; mean pulmonary arterial pressure, 41 +/- 2 mmHg; and systemic vascular resistance, 1,732 +/- 152 dynes.s/cm5. At infusion rates yielding comparable increases in the cardiac index (5 micrograms/kg/min for 2 hours for each drug), OPC-18790 produced significantly more favorable effects on heart rate (-2 +/- 3% vs 11 +/- 4%; P = .01), pulmonary capillary wedge pressure (-32 +/- 4% vs -17 +/- 8%; P = .04), mean pulmonary arterial pressure (-14 +/- 3% vs 6 +/- 11%; P = .06), stroke volume index (48 +/- 8% vs 29 +/- 7%; P = .02), stroke work index (70 +/- 11 vs 42% +/- 12%; P = .03), and rate pressure product (2 +/- 4% vs 14 +/- 4%; P = .05). The hemodynamic profile for OPC-18790 differs from dobutamine, with OPC-18790 exhibiting no increase in heart rate, greater preload reduction, and an increase in cardiac performance at a lower estimated metabolic cost.

Adrenergic beta-Antagonists↗
PubMed1992

Myocardial oxygen requirements during experimental cardiopulmonary resuscitation.

OBJECTIVE: The aims were to determine myocardial oxygen requirements during cardiopulmonary resuscitation (CPR), and to test the hypothesis that endogenous catecholamines have a major effect on myocardial oxygen requirements in this setting. METHODS: Myocardial oxygen consumption (MVO2) was measured during 20 minutes of CPR in eight anaesthetised dogs. Coronary blood flow was maintained at prearrest levels using an external pump to provide a permissive level of oxygen delivery during ventricular fibrillation. Oxygen content was measured in arterial and coronary sinus blood samples under prearrest conditions and at 5 min intervals during CPR. Four dogs were given propranolol (1 mg.kg-1) following the 5 min measurements. RESULTS: MVO2 averaged 108.7(SEM 12.8)% of the initial prearrest values after 5 min CPR (n = 8). After 10 min CPR, MVO2 fell to 53.8(13.3)% of the initial prearrest values in the subset of animals given propranolol after the 5 min measurements (n = 4), but remained at prearrest levels in untreated animals (p < 0.05 for an interactive effect between treatment and time). MVO2 subsequently tended to decrease with time in untreated animals, but remained a high percentage of prearrest values throughout the 20 min period of CPR. CONCLUSIONS: These findings suggest that endogenous sympathetic stimulation of the fibrillating heart results in high myocardial oxygen requirements during CPR.

Animals↗