Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators.

Bristow, Michael R.; O’Connell, John B.; Gilbert, Edward M.; French, William J.; Leatherman, George F.; Kantrowitz, Niki E.; Orie, Judith E.; Smucker, Mark L.; Marshall, Guillermo; Kelly, P. M.

doi:10.1161/01.cir.89.4.1632

Cited by 256 publications

(114 citation statements)

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“…Xamoterol, an agent with partial agonist activity, improved clinical status, exercise capacity, and overall quality of life but significantly increased mortality in patients with congestive heart failure. 30 Bucindolol also had significant beneficial effects on quality of life [31][32][33][34][35][36] but failed to improve mortality in a long-term trial. 12 The reasons for the failure of the BEST trial are not clear, but several explanations have been considered, including the possibility that ␤-adrenergic blockade is not beneficial for all subsets of patients.…”

Section: Discussionmentioning

confidence: 99%

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

et al. 2002

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Background-Most clinical studies have shown that ␤-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective ␤-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results-Myocardial strips (Ϸ1 mm3 ) obtained from rat and nonfailing human hearts were confirmed to be viable for Ն48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to ␤-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full ␤-adrenergic agonist isoproterenol raised cAMP levels by Ͼ2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by Ϸ25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64Ϯ0.25-fold and 2.00Ϯ0.27-fold over control, respectively, PϽ0.01 for human tissue). Conclusions-Bucindolol exhibits Ϸ60% of the ␤-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

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Section: Discussionmentioning

confidence: 99%

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

et al. 2002

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“…70 Both compounds were well tolerated in mild-moderate (NYHA class II or III) heart failure. 66 -73 As would be expected by ␤-blocker effects on maximal heart rate, maximal exercise tolerance was not improved in the majority of these studies, 66,67,69,70 but several showed improvement or favorable trends in submaximal exercise. 67,70,72 …”

Section: Discovery Of Functional ␤ 2 -Ars On Cardiac Myocytes In Humamentioning

confidence: 91%

“…115 In addition, because of blunting of exercise heart rate the higher doses of ␤-blockers that are associated with the best reverse remodeling effects do not improve functional capacity. 69,74,75 Therefore, although it is clear that restoration of cardiac reserve accessible by high doses of ␤-agonists occurs when receptor signal transduction is restored by ␤-blocking agents, 47 improved ␤-AR signal transduction does not appear to account for reverse remodeling and does not result in improved functional capacity. One conceptual framework for the cause of heart failure is to simply ascribe it to altered myocardial gene expression.…”

Section: Mechanism Of Action Of ␤-Blockers Inmentioning

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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“…51 In that trial, this nonselective vasodilating compound was well tolerated, 51 in marked contrast to previous 2,3 and subsequent 69 experiences with the nonselective first-generation agent propranolol. The second multicenter trial performed with a ␤-blocking agent was the bucindolol multicenter trial, 81 which was a phase 2 dose-response trial designed to select a dose of bucindolol to be used in phase 3 trials (Table 3). This trial had primary end points of left ventricular function and exercise tolerance, with secondary end points of quality of life and mortality.…”

Section: Bucindololmentioning

confidence: 99%