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107
Treatment of the Heart Failure Patient with Atrial Fibrillation: A Major Unmet Need
Bristow, MR et al.
Feb 1, 2013
Editorial emphasizing the lack of effective drug therapy for preventing recurrent atrial fibrillation in heart failure patients, emphasizing the ideal drug is one that prevents AF and improves heart failure.
Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias With Bucindolol in Patients With Chronic Heart Failure
Aleong, RG et al.
Dec 30, 2012
In an ADRB1 389 all-genotype population the prevention of new onset AF was similar to that reported for metoprolol succinate in MERIT-HF (by 43% in the BEST pharmacogenetic substudy, 47% in MERIT-HF), but in BEST the entire efficacy signal was in ADRB1 Arg389Arg patents (treatment effect vs. placebo = 74%, compared to -1% in ADRB! Gly carriers, interaction P=0.008). Since metoprolol exhibits no preference for treatment effects in Arg389 β1-ARs, in the ≈50% U.S. population who are ADRB1 Arg389Arg genotype, bucindolol would be expected to have a 74/47 or a 1.57 fold advantage in efficacy.
Combinatorial Pharmacogenetic Interactions of Bucindolol and β1, α2C Adrenergic Receptor Polymorphisms
O'Connor, CM et al.
Oct 10, 2012
Interactions of various combinations of ADRB1 Arg389Gly and ADRA2C Ins322-325Del genotypes in the BEST trial pharmacogenetic substudy indicated that for the primary endpoint and 5 secondary HF endpoints the ADRB1 Arg389Arg + any ADRA2C Indel combination genotype had the greatest bucindolol treatment effect, and that ADRB1 {Gly389 carriers + ADRA2C Del carrier combination genotypes had complete loss of efficacy with trends for increased cardiovascular mortality and more hospitalization days/patient. The latter was likely related to a greater reduction in norepinephrine (by 145±64 pg/ml) compared to ADRA2C Ins/Ins containing combinations (by -50±19 to 62±20 pg/ml). In contrast, the ADRB1 {Arg389Arg + ADRA2C Del carrier} combination, with an NE reduction of 120±82 pg/ml, exhibited the largest aggregated treatment effects (from 40-60% compared to placebo), consistent with the Arg389 β1-AR providing adequate support of cardiac function in the presence of a large reduction in NE. In contrast, the loss of function/lower NE affinity Gly389 β1-AR is unable to support function of the failing heart in the presence of a sudden and large reduction in NE.
Impact of the β1-adrenoceptor Arg389Gly Polymorphism on Heart-Rate Responses to Bisoprolol and Carvedilol in Heart-Failure Patients
Rau, T et al.
May 23, 2012
Randomized study in HF patients ≥65 yrs age comparing bisoprolol to carvedilol for rate control in SR or AF (CIBIS-ELD trial, N=883), with a 528 patient pharmacogenetic substudy. HR reduction in SR was not different between drugs or for ADRB1 Arg389Arg vs. Gly389 carrier genotypes, but in AF patients carvedilol treatment in the Arg389Arg genotype had significantly less HR reduction compared to Gly 389 carriers, or to bisoprolol treated patients with either genotype. These data indicate that AF rate control by carvedilol is suboptimal in AF patients with an ADRB1 Arg389Arg genotype and also indicate that unlike bucindolol (reference IIA2 above, Kao et al) carvedilol does not preferentially inhibit Arg389 β1-ARs.
Crystal Structures of a Stabilized β1-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol
Warne, T et al.
May 9, 2012
Crystal structure of the turkey β1-AR bound to the biased ligands bucindolol and carvedilol reveals unique but subtle binding contacts compared to other b-blockers, and the authors speculate that these may enhance β-arrestin binding.
Temporal analysis of mRNA and miRNA expression in transgenic mice overexpressing Arg- and Gly389 polymorphic variants of the β1-adrenergic receptor
Dockstader, K et al.
Dec 1, 2011
Transgenic cardiac overexpression of human Arg389 and Gly389 β1-ARs produces a dilated cardiomyopathy in Arg389 mice at 6-8 months but not at 3 mos, and no DCM in Gly389 animals at either timepoint. Changes in gene expression observed at 3 months in both Arg389 and Gly389 as well as in Gly389 at 6-8 months were qualitatively similar but more numerous in Arg389, suggesting that only the degree of downstream signaling is different between the 2 β1-AR variants.
Treatment of Chronic Heart Failure with β-adrenergic Receptor Antagonists: A Convergence of Receptor Pharmacology and Clinical Cardiology
Bristow, MR
Oct 28, 2011
This paper gives the history of the development of β-blockade as a treatment for HFrEF and includes a comparison of BEST mortality results with COPERNICUS under the same entry criteria (virtually identical effects on mortality reduction). A review of basic mechanisms indicates that the β1-AR pathway is more biologically adverse than β2, but that β2-AR signaling also has adverse biologic potential.
An α2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the β-Blocker Bucindolol in Chronic Heart Failure
Bristow, MR et al.
Oct 30, 2009
The Del polymorphism in ADRA2C dysregulates norepinephrine release, and in BEST is associated with greater NE reduction by bucindolol when compared to heart failure patients who are ADRA2C Ins/Ins.
β-Arrestin Mediates β1-Adrenergic Receptor-Epidermal Growth Factor Receptor Interaction and Downstream Signaling
Tilley, DG et al.
Jul 24, 2009
The details of how β1-AR occupancy by agonists and biased ligands leads to EGFR transactivation and ERK1/2 activation are investigated in non-myocyte cell cultures. On agonist occupancy β1-AR and EGFR form a receptor complex at the plasma membrane, leading to both receptors being phosphorylated and β-arrestin recruitment to the receptor complex. This leads to receptor complex internalization and activation of downstream signaling culminating in ERK1/2 phosphorylation.
The role of third generation β-blocking agents in chronic heart failure
Bristow, MR et al.
Feb 3, 2009
The paper contains a description of the 3rd generation b-blockers as nonselective β1/β2- (bucindolol, carvedilol) or selective β1-AR (nebivolol) competitive antagonists with vasodilator activity. Newly presented data demonstrated that neither bucindolol nor carvedilol has intrinsic sympathomimetic activity. Both agents are well-tolerated, unlike nonselective b-blockers without vasodilator properties such as propranolol; the intolerance of propranolol in heart failure patients had led to the conclusion that b-blockers are contraindicated in heart failure.
A polymorphism of G-protein coupled receptor kinase5 alters agonist-promoted desensitization of β2-adrenergic receptors
Wang, WC et al.
Aug 1, 2008
G-protein coupled receptor 5 (GRK5) has a gain of function nonsynonymous SNP at codon 41 (Gln41Leu) that is much more common in African ancestry subjects, and which is associated with greater degrees of β2-AR phosphorylation and internalization.
Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated with Carvedilol or Metoprolol
Sehnert, AJ et al.
Aug 1, 2008
Unlike for bucindolol in BEST, neither carvedilol- or metoprolol-treated HFrEF patients show any evidence for differences in outcomes for either ADRB1-389, ADRB1-49, ADRB2-16, ADRB2-27, or ADRA2C Indel polymorphisms.
Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased Mitogen-Activated Protein Kinase Signaling through the β1-Adrenergic Receptor
Galandrin, S et al.
Jul 1, 2008
Isoproterenol activates the MAPK ERK1/2 pathway by both Gs and Gs independent signaling; the biased ligand bucindolol and the neutral antagonist propranolol phosphorylate ERK1/2 only by Gs independent signaling.
A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signaling
Wisler, JW et al.
Oct 16, 2007
In HEK293 cells stably expressing human β2-ARs carvedilol did not stimulate cAMP production, but did phosphorylate the cytoplasmic tail at GRK sites, recruited b-arrestin to the receptor, internalized the receptor, and activated ERK1/2 phosphorylation. Thus, carvedilol is a biased ligand at human β2-ARs if agonist properties other than cAMP stimulation are measured.
Recombinant Nematode Anticoagulant Protein c2 in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome: The ANTHEM–TIMI-32 Trial
Giugliano, RP et al.
Jun 1, 2007
Phase 2 dose ranging and safety trial (N=203) of rNAPc2 randomized 4:1 vs. placebo in nSTEMI ACS, administered in addition to standard other treatments including PCI, with thrombolysis an exclusion. rNAPc2 had an acceptable adverse event profile.
Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis
Nasr, IA et al.
Feb 8, 2007
Meta-analysis of effects of β-blockers preventing AF in 5 heart failure and 1 post MI trial. In trials with an evaluable number of events only 2 drugs showed statistically significant benefit: bucindolol in BEST (31% risk reduction) and metoprolol succinate in MERIT-HF (39% risk reduction).
Distinct Signaling Profiles of β1 and β2 Adrenergic Receptor Ligands toward Adenylyl Cyclase and Mitogen-Activated Protein Kinase Reveals the Pluridimensionality of Efficacy
Galandrin, S et al.
Nov 1, 2006
Human β1- and β2-AR were stably transfected into HEK293 cells and compounds were tested for their abilities to activate both the cAMP and MAP kinase /Erk1/2 pathways. In β1-ARs Bucindolol and carvedilol activated both pathways, at the 20-40% of isoproterenol levels, whereas metoprolol, bisoprolol and atenolol did not. Thus under these conditions, in pharmacologic current terminology, bucindolol and carvedilol are “biased ligands” for the β1-AR, partially activating 2 separate pathways through the same receptor. For Erk1/2 activation bucindolol was 5 fold more potent than carvedilol, but with equal efficacy (maximal response 25% of the isoproterenol effect). For β2-ARs neither bucindolol nor carvedilol activated the adenylate cyclase/cAMP pathway, but they did activate ERK1/2 signaling with bucindolol’s efficacy being 65% and carvedilol’s 38% of isoproterenol’s, with bucindolol 7 times more potent. Metoprolol, bisoprolol and atenolol did not activate ERK1/2 signaling in b2-AR containing cells. Thus, bucindolol and carvedilol are not technically biased ligands for β2-ARs, but do activate ERK1/2 signaling to a greater extent than their activation in β1-ARs.
A β1-adrenergic receptor, CaM Kinase II dependent pathway mediates cardiac myocyte fetal gene induction
Sucharov, CC et al.
Sep 1, 2006
In cardiac myocytes Isoproterenol via β1-AR signaling through CaMKII mediates the mRNA induction of fetal isoforms for myosin heavy chain and cardiac actin, increases ANP and decreases SR Ca2+ ATPase.
A polymorphism within a conserved β1-adrenergic receptor motif alters cardiac function and β-blocker response in human heart failure
Liggett, SB et al.
Jul 25, 2006
In BEST trial patients with an ADRB1 Arg389Arg genotype bucindolol exhibits greater efficacy for reduction in heart failure endpoints including the primary endpoint of all-cause mortality or cardiac transplantation, compared to counterpart Gly389 genotypes.
β2-Adrenergic Receptor Genotype and Survival Among Patients Receiving β-Blocker Therapy After an Acute Coronary Syndrome
Lanfear, DE et al.
Sep 28, 2005
ADRB1 and ADRB2 genotypes and ADRB2 haplotypes were determined in acute coronary syndrome patients admitted for hospitalization, and post discharge mortality was compared in those discharged on β-blockers (N=597) and those not prescribed β-blockers (N=138). In patients receiving β-blockers no effects on mortality were detected by ADRB1 genotypes, but ADRB2 genotypes were associated with differences in mortality (Gln/27/Gln higher vs Glu27Glu, heterozygotes intermediate, P=0.004). Arg16 Arg genotype had higher mortality than Gly16/Gly, with heterozygotes intermediate, P=0.005. For ADRB2 haplotypes, the inferred diplotypes of Glu27Gly16 were low risk and Gln27Arg16 high risk, with other haplotype combinations intermediate (overall P=0.002).
Ser49Gly of β1-adrenergic receptor is associated with effective β-blocker dose in dilated cardiomyopathy
Magnusson, Y et al.
Sep 4, 2005
ADRB1 Gly49 (the internalizing variant) genotype was associated with reduced mortality compared to Ser49 in patients treated with low doses of β-blockers, but no difference was observed with high doses. This is compatible with Gly49 having a favorable effect on outcomes in no or low dose β-blocker therapy.
Effect of Baseline or Changes in Adrenergic Activity on Clinical Outcomes in the Beta-blocker Evaluation of Survival Trial (BEST)
Bristow, MR et al.
Aug 30, 2004
Bucindolol’s sympatholytic effects (lowering of peripheral venous norepinephrine (NE) levels) in BEST were highlighted. NE changes were associated with a U-shaped effect on outcomes consisting of moderate reduction indicating benefit but loss of efficacy with no change or larger decreases.
Functional responses of human β1 adrenoceptors with defined haplotypes for the common 389R>G and 49S>G polymorphisms
Sandilands, A et al.
Jun 1, 2004
The 4 ADRB1 c49 and c389 haplotypes were stably transfected into HEK293 cells and pharmacologically characterized. Rapid desensitization and downregulation tracked with the presence of Gly 49 within either the Arg or Gly389 haplotype, and maximal adenylate cyclase stimulation by isoproterenol tracked with the presence of Arg389 regardless of a Gly or Ser on codon 49. However, 20 hrs of pre-incubation with isoproterenol reversed the position of the subsequent Iso dose-response curve generated after 10 minutes of Iso incubation, from Arg389Gly49 > Arg389Gly49 to Arg389Ser49 > Arg389Gly49. This was likely because of downregulation in Arg389Gly49 receptors at 20 hours, probably as a result of greater internalization and lysosomal degradation. The authors use the data for arguing that receptor haplotypes can yield different information than individual polymorphism genotype, and that “further association studies with the β1-AR should take into account both the 49 and 389 polymorphisms”.