Publications
Documents & Other Announcements
Results:
107
Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents
Lowes, BD et al.
Dec 3, 2003
The previously predicted basis for β-blocker reverse remodeling being due to favorable effects on gene expression is confirmed, with metoprolol tartrate and carvedilol both producing reverse remodeling associated with reversal of isoforms of contractility and hypertrophy-related genes from a fetal to an adult pattern and upregulation in SR Ca2+ ATPase, a major contractility regulating gene. There was no difference between metoprolol and carvedilol in either degree of reverse remodeling or changes in gene expression.
A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS
Domanski, MJ et al.
Oct 1, 2003
BEST trial data are compared to 3 other β-blocker mortality trials using the same entry criteria, and the results are not different among the 4 trials for total mortality or mortality subtypes.
Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor
Lee, AY et al.
Sep 15, 2003
Review of the discovery and cloning from hookworm saliva of the 85 amino acid protein rNAPc2, and its anticoagulation and anti-inflammatory mechanism of action in inhibiting the PAR2 pathway.
β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure
Mialet Perez, J et al.
Sep 14, 2003
Cardiac transgenic overexpression of ADRB1 Arg vs Gly 389 in mice creates more cardiomyopathic changes, with higher LV function and evidence of constitutive activity.
Protein Kinase A and G Protein-coupled Receptor Kinase Phosphorylation Mediates β-1 Adrenergic Receptor Endocytosis through Different Pathways
Rapacciuolo, A et al.
Sep 1, 2003
For β1-ARs PKA-mediated phosphorylation directs internalization via a caveolae pathway, whereas GRK-mediated phosphorylation directsinternalization through clathrin-coated pits.
An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study
White, HL et al.
Aug 11, 2003
In the MERIT-AF trial pharmacogenetic substudy (N=600), no effect of the ADRB1 Arg389Gly polymorphism was observed on the endpoint of all-cause mortality or hospitalization, or on the response to metoprolol.
Synergistic Polymorphisms of β1- and α2C-Adrenergic Receptors and the Risk of Congestive Heart Failure
Small, KM et al.
Oct 10, 2002
African ancestry heart failure patients who are homozygous for ADRA2C Del322-325 and ADRB1 Arg389Arg have a 10-fold increase in developing heart failure compared to other genotypes.
Complexity of Agonist- and Cyclic AMP-Mediated Downregulation of the Human β1-Adrenergic Receptor: Role of Internalization, Degradation, and mRNA Destabilization
Dunigan, CD et al.
May 30, 2002
Factors regulating internalization and downregulation of human β1-ARs (and in some experiments β2) stably transfected into Chinese hamster fibroblasts were investigated. For agonist (isoproterenol) mediated downregulation both internalization and endosomal trafficking, presumably to lysosomes (inhibited by leupeptin) as well as a mRNA destabilization (cAMP dependent) was found; same for β2-ARs.
Amino Acid 49 Polymorphisms of the Human β1-Adrenergic Receptor Affect Agonist-Promoted Trafficking
Rathz, DA et al.
Feb 1, 2002
In HEK293 cells stably transfected with human β1-Ser49 and -Gly49 ARs, isoproterenol incubation for 30 minutes produced the same degree (27-28%) of internalization in both receptor subtypes, but on 24 hrs of isoproterenol incubation only Gly49 b1-ARs downregulated suggesting differences in post-internalization trafficking of the 2 variants, or greater longer term (than 30 min) internalization of Gly49 β1-ARs (not measured in this study).
The Effect of Common Polymorphisms of the β2-Adrenergic Receptor on Agonist-Mediated Vascular Desensitization
Dishy, V et al.
Oct 4, 2001
In human healthy volunteers a hand vein isoproterenol dose-response for vasodilation was measured before and after a 2 hour infusion of isoproterenol to detect desensitization. Patients with an ADRB2 Gln27Arg16 haplotype desensitized, while the alternative Gln27Gly16 and Glu27Gly16 haplotypes did not. The desensitization response is likely related to receptor internalization (sequestration away from the cell surface membrane).
Bucindolol, a Nonselective β1- and β2-Adrenergic Receptor Antagonist, Decreases β-Adrenergic Receptor Density in Cultured Embryonic Chick Cardiac Myocyte Membranes
Asano, K et al.
Jun 1, 2001
In avian cultured cardiac myocyte β1-ARs incubated for 24 hrs with an agonist (norepinephrine, (NE)) or the biased ligands bucindolol (Buc) or carvedilol (Crv), NE produced downregulation in receptor protein and mRNA, Buc was associated with receptor downregulation but no change in mRNA abundance, and Crv produced no change in receptor density or mRNA abundance. These data are consistent with a greater degree of internalization by Buc compared to Crv, leading to receptor degradation unrelated to any change in mRNA abundance. For NE both internalization and mRNA abundance may be involved in receptor downregulation. Similar results for Buc and Crv were obtained smooth muscle cell β2-ARs.
A Trial of the Beta-Adrenergic Blocker Bucindolol in Patients with Advanced Heart Failure
BEST Investigators
May 31, 2001
BEST trial stopped prematurely because of “loss of investigator equipoise” due to MERIT-HF results being public, results in Class III HF being similar to those in the MERIT-HF trial and results in the enrollment-enriched Black population showing no evidence of benefit.
Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness
Drysdale, CM et al.
Sep 12, 2000
ADRB2 haplotypes were defined and compared by albuterol physiologic bronchodilator response, and receptor protein and mRNA expression in transfected cells. Compared to Glu27Gly16 homozygote diplotypes, Gln27Arg16 homozygote diplotypes had lower bronchodilator response and receptor protein or mRNA expression.
A Four Amino Acid Deletion Polymorphism in the Third Intracellular Loop of the Human α2C-Adrenergic Receptor Confers Impaired Coupling to Multiple Effectors
Small, KM et al.
Jul 1, 2000
A 12 nt deletion in the ADRA2C gene creates a 3rd cytoplasmic loop 4 amino acid deletion (ADRA2C 322-32d InDel) that creates near complete loss of function in the α2C-AR, which ordinarily tonically inhibits norepinephrine release in adrenergic neurons and functions in regulating release in response to bucindolol. The minor allele (Del) frequency is highly race dependent, ranging from 40% in African ancestry to 4 % in European ancestry.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
MERIT-HF Study Group
Jun 12, 1999
In a 3991 patient HFrEF study in mild-moderate HFrEF (Class II, III, LVEF <0.40), compared to placebo, metoprolol succinate decreased mortality and all types of hospitalizations.
A Gain-of-function Polymorphism in a G-protein Coupling Domain of the Human β1-Adrenergic Receptor
Mason, DA et al.
Apr 1, 1999
Identification and pharmacologic characterization of a common nonsynonymous SNP at ADRB1 nt1165 that creates an Arg389Gly polymorphism at codon 389, with a minor (Gly) allele frequency of ≈30%. Compared to Arg389 the Gly389 β1-AR exhibits loss of function, with lower affinity for agonist binding and reduced signal transduction capacity.
Essential Role for G Protein-coupled Receptor Endocytosis in the Activation of Mitogen-activated Protein Kinase
Daaka, Y et al.
Jan 1, 1998
In HEK293 cells stably transfected with human β2-ARs a dominant suppressor mutant of dynamin abolished isoproterenol induced internalization and MAPK ERK1/2 activation, indicating that internalization is essential for MAPK activation.
Clathrin-mediated Endocytosis of the β-Adrenergic Receptor Is Regulated by Phosphorylation/Dephosphorylation of β-Arrestin1
Lin, FT et al.
Dec 1, 1997
β2-AR Internalization sequence of events identified as 1) receptor phosphorylation, 2) recruitment of β-arrestin1 to the phosphorylated receptor, 3) bound β-arrestin1 uncouples the receptor from G proteins, 4) β-arrestin1 bound receptor internalizes, with β-arrestin1 serving as a clathrin adaptor targeting the receptor for internalization
Second- and Third-Generation Beta-Blocking Drugs in Chronic Heart Failure
Bristow, MR et al.
May 1, 1997
A comparison of Phase 2 HFrEF trial data for LV remodeling, LV function, hemodynamic and norepinephrine effects for metoprolol, bucindolol and carvedilol indicated greater reverse remodeling for bucindolol and carvedilol compared to metoprolol, more improvement in LV systolic function with bucindolol, and bucindolol as the only agent that lowered norepinephrine compared to placebo.
Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects with Chronic Heart Failure
Bristow, MR et al.
Dec 1, 1996
In addition to working with bucindolol Dr. Bristow had been performing preclinical and Phase II studies with carvedilol, a similar 3rd generation nonselective beta-blocker vasodilator activity with more potent a1-AR blocking and vasodilator activity. When carvedilol’s U.S. sponsor, SKB, learned that bucindolol was going to Phase 3 they also decided to move forward, but in more mild (Class II, III) HFrEF with a program of 2 pivotal and 2 smaller supportive trials (the “U.S. Carvedilol Program”) based on the primary endpoint of submaximal exercise. The four trials were followed by a single data and safety monitoring committee that included mortality as a safety endpoint, but not as an efficacy parameter. Submaximal exercise was not positive in any of the trials, but in one of the Phase 3 trials, MOCHA, a 6 month dose response study similar in dosing to what had been done with bucindolol in Phase 2, there was a marked decrease in mortality (by 73%, P <0.001 based on 25 total deaths) and an increase in LVEF that were both dose related, as well as a decrease in cardiovascular hospitalizations, a secondary efficacy endpoint. In the 4 trials combined there was a 65% decrease (P <0.001) in mortality based on 53 deaths, and a 27% decrease in cardiovascular hospitalizations (P=0.036) based on 176 total events (Packer M, Bristow MR et al NEJM 1996). Carvedilol was eventually approved in 1997 for mild-moderate HFrEF treatment on the basis of a post hoc combined endpoint of mortality and cardiovascular hospitalization, after being initially rejected based on the failure to meet the submaximal exercise primary endpoint. A properly designed mortality trial subsequently confirmed the MOCHA and U.S. Carvedilol reduction in mortality (Packer et al, NEJM 2002).
Medical Therapy Can Improve the Biologic Properties of the Chronically Failing Heart: A New Era in the Treatment of Heart Failure
Eichhorn EJ, Bristow MR
Nov 1, 1996
Based on the ability of β-blockers to reverse remodeling and increase contractile function after initially transiently depressing myocardial performance on dose initiation, Eichhorn and Bristow declare a new era in the treatment of heart failure that is based on biologic improvement, most likely due to favorable changes in myocardial gene expression. Reverse Remodeling is proposed to be the major beneficial mechanism of β-blocker therapy in failing left ventricles with eccentric remodeling.
Design of the Beta-Blocker Evaluation Survival Trial (BEST)
BEST Steering Committee
Jun 15, 1995
In 1994 Drs. Eichhorn, Bristow et al received a grant from the VA Cooperative Studies Program (VA CSP) to perform the Beta-blocker Evaluation of Survival Trial (BEST), the first mortality trial with a b-blocker in HFrEF. Tthe NHLBI then asked asks to join and bucindolol was outlicensed from Bristol Myers to Intercardia, Inc. The approved protocol was agnostic to the b-blocker, and the trial Steering Committee choose bucindolol in competition with carvedilol and metoprolol succinate, on the basis of the quantity and quantity of Phase 2 data. Because the primary endpoint was all-cause mortality Class III or IV HFrEF (LVEF ≤0.35) was a major entry criterion, in order to ensure a high enough event rate at a reasonable sample size. BEST was thus the first β-blocker mortality trial to be planned and launched, with the first patient enrolled in May, 1995.