An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure

Michael R. Bristow, Guinevere A. Murphy, Heidi Krause-Steinrauf, Jeffrey L. Anderson, John F. Carlquist, Surai Thaneemit-Chen, Vaishali Krishnan, William T. Abraham, Brian D. Lowes, J. David Port, Gordon W. Davis, Laura C. Lazzeroni, Alastair D. Robertson, Phillip W. Lavori, Stephen B. Liggett

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Background-Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional α2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel β-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether α2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results-In the β-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and α2C-AR gene polymorphisms (α2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were α2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153 ±57 pg/mL, P=0.012 compared with placebo versus decrease of 50± 13 pg/mL in α2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). α2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the α2C-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025). Conclusions-In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by α2C receptor genotype.

Original languageEnglish (US)
Pages (from-to)21-28
Number of pages8
JournalCirculation: Heart Failure
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2010

Fingerprint

Therapeutic Uses
Adrenergic Receptors
Norepinephrine
Heart Failure
Sympatholytics
Placebos
Adrenergic Agents
Survival
Adrenergic Antagonists
Mortality
Homozygote
Heterozygote
bucindolol
Electrophoresis
Gels
Genotype
Polymerase Chain Reaction
DNA
Genes

Keywords

  • Adrenergic
  • Alpha
  • Genetics
  • Heart failure
  • Norepinephrine
  • Receptors
  • β-blockers

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure. / Bristow, Michael R.; Murphy, Guinevere A.; Krause-Steinrauf, Heidi; Anderson, Jeffrey L.; Carlquist, John F.; Thaneemit-Chen, Surai; Krishnan, Vaishali; Abraham, William T.; Lowes, Brian D.; Port, J. David; Davis, Gordon W.; Lazzeroni, Laura C.; Robertson, Alastair D.; Lavori, Phillip W.; Liggett, Stephen B.

In: Circulation: Heart Failure, Vol. 3, No. 1, 01.01.2010, p. 21-28.

Research output: Contribution to journalArticle

Bristow, MR, Murphy, GA, Krause-Steinrauf, H, Anderson, JL, Carlquist, JF, Thaneemit-Chen, S, Krishnan, V, Abraham, WT, Lowes, BD, Port, JD, Davis, GW, Lazzeroni, LC, Robertson, AD, Lavori, PW & Liggett, SB 2010, 'An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure', Circulation: Heart Failure, vol. 3, no. 1, pp. 21-28. https://doi.org/10.1161/CIRCHEARTFAILURE.109.885962
Bristow, Michael R. ; Murphy, Guinevere A. ; Krause-Steinrauf, Heidi ; Anderson, Jeffrey L. ; Carlquist, John F. ; Thaneemit-Chen, Surai ; Krishnan, Vaishali ; Abraham, William T. ; Lowes, Brian D. ; Port, J. David ; Davis, Gordon W. ; Lazzeroni, Laura C. ; Robertson, Alastair D. ; Lavori, Phillip W. ; Liggett, Stephen B. / An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure. In: Circulation: Heart Failure. 2010 ; Vol. 3, No. 1. pp. 21-28.
@article{64bef8229cf14f138d58905baa2a06f2,
title = "An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure",
abstract = "Background-Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional α2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel β-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether α2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results-In the β-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and α2C-AR gene polymorphisms (α2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were α2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153 ±57 pg/mL, P=0.012 compared with placebo versus decrease of 50± 13 pg/mL in α2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). α2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95{\%} CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the α2C-AR had a 30{\%} reduction in mortality (hazard ratio, 0.70; 95{\%} CI, 0.51 to 0.96; P=0.025). Conclusions-In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by α2C receptor genotype.",
keywords = "Adrenergic, Alpha, Genetics, Heart failure, Norepinephrine, Receptors, β-blockers",
author = "Bristow, {Michael R.} and Murphy, {Guinevere A.} and Heidi Krause-Steinrauf and Anderson, {Jeffrey L.} and Carlquist, {John F.} and Surai Thaneemit-Chen and Vaishali Krishnan and Abraham, {William T.} and Lowes, {Brian D.} and Port, {J. David} and Davis, {Gordon W.} and Lazzeroni, {Laura C.} and Robertson, {Alastair D.} and Lavori, {Phillip W.} and Liggett, {Stephen B.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1161/CIRCHEARTFAILURE.109.885962",
language = "English (US)",
volume = "3",
pages = "21--28",
journal = "Circulation: Heart Failure",
issn = "1941-3289",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure

AU - Bristow, Michael R.

AU - Murphy, Guinevere A.

AU - Krause-Steinrauf, Heidi

AU - Anderson, Jeffrey L.

AU - Carlquist, John F.

AU - Thaneemit-Chen, Surai

AU - Krishnan, Vaishali

AU - Abraham, William T.

AU - Lowes, Brian D.

AU - Port, J. David

AU - Davis, Gordon W.

AU - Lazzeroni, Laura C.

AU - Robertson, Alastair D.

AU - Lavori, Phillip W.

AU - Liggett, Stephen B.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Background-Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional α2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel β-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether α2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results-In the β-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and α2C-AR gene polymorphisms (α2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were α2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153 ±57 pg/mL, P=0.012 compared with placebo versus decrease of 50± 13 pg/mL in α2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). α2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the α2C-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025). Conclusions-In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by α2C receptor genotype.

AB - Background-Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional α2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel β-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether α2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results-In the β-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and α2C-AR gene polymorphisms (α2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were α2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153 ±57 pg/mL, P=0.012 compared with placebo versus decrease of 50± 13 pg/mL in α2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). α2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the α2C-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025). Conclusions-In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by α2C receptor genotype.

KW - Adrenergic

KW - Alpha

KW - Genetics

KW - Heart failure

KW - Norepinephrine

KW - Receptors

KW - β-blockers

UR - http://www.scopus.com/inward/record.url?scp=76549133595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76549133595&partnerID=8YFLogxK

U2 - 10.1161/CIRCHEARTFAILURE.109.885962

DO - 10.1161/CIRCHEARTFAILURE.109.885962

M3 - Article

C2 - 19880803

AN - SCOPUS:76549133595

VL - 3

SP - 21

EP - 28

JO - Circulation: Heart Failure

JF - Circulation: Heart Failure

SN - 1941-3289

IS - 1

ER -