Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Abstract

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...

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

“…33 This excessive SNS activity results in sustained bAR activation and consequent desensitization and downregulation. Ventricular remodeling is reinforced by progressive catecholamine-induced myocyte cell death, resulting in cardiac deterioration, and changes in ventricular mass promote ventricular dilation and failure.…”

“…Ventricular remodeling is reinforced by progressive catecholamine-induced myocyte cell death, resulting in cardiac deterioration, and changes in ventricular mass promote ventricular dilation and failure. 33,34 Although b-blockers only indirectly address key molecular signaling alterations within the cardiac myocyte, their clinical use substantially improved HF prognosis, and they are thus considered a solid rock in HF treatment. Interestingly, molecular alterations observed with sustained therapeutic effects of b-blockade in HF include resensitization of bARs, normalization of GRK2 levels and activity and Ga levels.…”

“…First, nonselective b-blockers like propranolol antagonize the catecholamine activation of both b 1 AR and b 2 AR expressed in the heart. 33 The second type of b-blockers (for example, metroprolol and bisoprolol) have much greater affinity for b 1 AR than for b 2 AR and are thus considered 'cardioselective' . 33 The third type of b-blockers provide a broader anti-adrenergic effect than type 2 blockers because of the fact that its members, carvedilol and bucindolol, possess vasodilatory properties by blocking vascular aARs as well as the ability to reduce cardiac and systemic adrenergic drive.…”

“…33 The second type of b-blockers (for example, metroprolol and bisoprolol) have much greater affinity for b 1 AR than for b 2 AR and are thus considered 'cardioselective' . 33 The third type of b-blockers provide a broader anti-adrenergic effect than type 2 blockers because of the fact that its members, carvedilol and bucindolol, possess vasodilatory properties by blocking vascular aARs as well as the ability to reduce cardiac and systemic adrenergic drive. 33 Several large prospective, randomized, placebo-controlled trials have provided evidence for sustained therapeutic clinical effects of b-blockers.…”

“…33 The third type of b-blockers provide a broader anti-adrenergic effect than type 2 blockers because of the fact that its members, carvedilol and bucindolol, possess vasodilatory properties by blocking vascular aARs as well as the ability to reduce cardiac and systemic adrenergic drive. 33 Several large prospective, randomized, placebo-controlled trials have provided evidence for sustained therapeutic clinical effects of b-blockers. 33 This includes demonstration of improved quality of life and, even more importantly, reduction of cardiovascular mortality and risk of sudden death.…”