Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated With Carvedilol or Metoprolol

Sehnert, Amy J.; Daniels, Susan E.; Elashoff, Michael; Wingrove, James A.; Burrow, Christopher R.; Horne, Benjamin D.; Muhlestein, Joseph B.; Donahue, Mark; Liggett, Stephen B.; Anderson, Jeffrey L.; Kraus, William E.

doi:10.1016/j.jacc.2008.05.022

Cited by 121 publications

(100 citation statements)

References 29 publications

(30 reference statements)

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“…Within the MERIT-HF enrollment criteria (BEST Comparison Group, BCG) the differential response between genotypes is even more pronounced, with an Arg/Arg versus Gly carrier hazard ratio of 0.59 (0.40, 0.87; Pϭ0.007) in the bucindolol group versus a nonsignificant hazard ratio of 1.02 in the placebo group. Another relatively large study (nϭ637) also has shown no ␤ 1 389 Arg versus Gly differentiation of clinical response to metoprolol, or carvedilol, 166 and there are no reports that metoprolol or carvedilol clinical end point responses are affected by the ␤ 1 389 Arg/Gly genotype. This likely means that the basis for bucindolol's differentiation is its unique pharmacological properties of ␤ 1 389 Arg inverse agonism 157 and NE lowering.…”

Section: Polymorphic Variation In ␤ 1 -And ␤ 2 -Arsmentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

151

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ReviewTranslational Success Stories highlight how basic discoveries have led to clinical advances (such as the use of new drugs or diagnostic modalities in patients). This initiative reflects the renewed emphasis of our journal on translational research. It is hoped that these articles will stimulate efforts to translate basic insights into clinical practice. Treatment of Chronic Heart Failure With ␤-AdrenergicReceptor Antagonists A Convergence of Receptor Pharmacology and Clinical CardiologyMichael R. BristowAbstract: Despite the absence of a systematic development plan, ␤-blockers have reached the top tier of medical therapies for chronic heart failure. The successful outcome was due to the many dedicated investigators who produced, over a 30-year period, increasing evidence that ␤-blocking agents should or actually did improve the natural history of dilated cardiomyopathies and heart failure. It took 20 years for supportive evidence to become undeniable, at which time in 1993 the formidable drug development resources of large pharmaceutical companies were deployed into Phase 3 trials. Success then came relatively quickly, and within 8 years multiple agents were on the market in the United States and Europe. Importantly, there is ample room to improve antiadrenergic therapy, through novel approaches exploiting the nuances of receptor biology and/or intracellular signaling, as well as through pharmacogenetic targeting. (Circ Res. 2011;109:1176-1194.)Key Words: heart failure Ⅲ adrenergic receptors Ⅲ ␤-blockers Ⅲ norepinephrine Ⅲ drug development "I love it when a plan comes together" -Colonel John "Hannibal" Smith, The A-Team ␤ -Adrenergic blocking agents are now considered firstline therapy for chronic heart failure. 2 Between 1971 and 2001, ␤-blockers as a drug class went from contraindicated to being universally declared a highly effective new therapy for chronic heart failure with systolic dysfunction. As depicted in Figure 1, this 180-degree turn required the convergence of initially disconnected lines of basic and clinical investigation, none of which was systematically planned by the usual purveyors of drug development, large pharmaceutical companies. However, as for the typical outcome of Colonel Hannibal Smith's unconventional and dubious tactical schemes, 1 the end result was highly successful. This review provides some of the historical highlights, summarizes current knowledge, and provides thoughts on the future of ␤-blocker and antiadrenergic therapy. Historical Highlights Discovery of Adrenergic ReceptorsIn 1948, Raymond Ahlquist reported evidence for two types of adrenergic receptors, 3 which, "for convenience," he termed alpha and beta. The evidence was based on 2 distinct rank orders of agonist potency for a variety of pharmacological responses, plus the ability to inhibit the vasoconstrictor or uterine contraction responses of the ␣ group, with 3 different compounds (dibenamine, ergotoxine, or tolazoline) that would later be termed ␣-blocking agents. At the time of Ahlquist's landmark work, the...

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Section: Polymorphic Variation In ␤ 1 -And ␤ 2 -Arsmentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

151

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“…No difference in survival rates Sehnert et al, 2008 Gene structure and proposed three-dimensional structure of G␤3 and its splice variants, G␤3s and G␤3s2. Top, the G␤3 gene consists of 11 exons; coding exons are indicated in black.…”

Section: Lobmeyer Et Al 2007mentioning

confidence: 99%

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Rosskopf

Michel²

2008

Pharmacol Rev

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“…First, the as- sociation of these polymorphisms with heart failure susceptibility and prognosis is controversial. 11, 21 One possible reason for the inconsistencies between studies is the low sample numbers used, as in this study. The present results should be compared with those of larger studies.…”

Section: Study Limitationsmentioning

confidence: 91%