Antiadrenergic therapy of chronic heart failure: surprises and new opportunities.

The great British-American scientist-philosopher Alfred North Whitehead divided progress into three stages, the second of which was termed precision, in which the “right ways and wrong ways” of an original idea are elucidated.1 During this period, reinterpretation of the basic idea occurs and is essential to progress. Whitehead’s message is that important ideas are dynamic instruments that are constantly changing as new and usually unexpected information becomes available. This is why tests of particular hypotheses, including those tested in Phase III clinical trials, are often unsupportive, and why therapeutic paradigms constantly change. Within such an ephemeral milieu, the key to ultimate success is to view each unexpected or negative result as an opportunity for constructing and testing even more novel and valuable hypotheses within the framework of the general idea, to ascend to the final stage where progress can be “generalized.”1 Whitehead’s philosophical legacy is impressively in play in the area of antiadrenergic therapy of chronic heart failure (CHF). The unarguable basic idea is that the biologically powerful adrenergic compensatory mechanism plays a critical role in the natural history of CHF. It is the details or nuances within the general paradigm that continue to change, and lately, surprisingly so. As recently reviewed,2 the importance of dysfunctional adrenergic activation in CHF was first elucidated by work performed by Braunwald’s group at the National Institutes of Health in the 1960s. Among other things, this early work provided the first evidence of marked adrenergic activation in CHF. However, on the basis of reduction in myocardial tissue norepinephrine, and the shortterm effects of large doses of antiadrenergic agents,3 the overall interpretation was that adrenergic support was deficient in CHF. This view prevailed for 10 to 15 years, and it contributed to the original logic behind developing Type III phosphodiesterase inhibitors as a treatment for CHF. In the late 1970s and early 1980s, three separate lines of evidence contributed to a 180-degree turn in the role of adrenergic mechanisms in CHF. As recently summarized,4 these paradigm-changing observations were: (1) the apparently favorable clinical response to -blocking agents when administered chronically to subjects with idiopathic dilated cardiomyopathies; (2) the evidence that the failing human heart exhibited -adrenergic receptor downregulation and pathway desensitization, which are typical responses to excessive exposure to adrenergic drive; and (3) the demonstration that coronary sinus norepinephrine levels were elevated in CHF patients, reflecting an increase in interstitial levels despite the decrease in tissue stores. For the next 15 to 20 years, the prevailing view was that excessively and incessantly increased adrenergic drive is uniformly harmful to the natural history of primary or secondary dilated cardiomyopathies and to the CHF clinical syndrome.4 This refinement predicts that any treatment that reduces adrenergic activation would produce favorable effects on CHF natural history. However, results of recently completed clinical trials are not consistent with this general paradigm. An agent that powerfully lowers norepinephrine through central imidazoline and/or 2-adrenergic receptor activation plus possible presynaptic 2-receptor agonism, moxonidine, increased mortality by 50% in the Moxonidine Congestive Heart Failure (MOXCON) Trial, with the study being terminated for safety concerns after 1000 patients were enrolled.5 In phase II this compound was powerfully sympatholytic, and the degree of systemic norepinephrine reduction was directly associated with an increase in serious adverse events despite evidence for reverse remodeling, the signature of favorable antiadrenergic effects on the failing heart.6 Because sympatholysis is the only known important pharmacological property of moxonidine, these data seriously challenged the uniform dogma that antiadrenergic therapy is beneficial. That sympatholysis is a harmful pharmacological property in a therapeutic agent used to treat CHF is further supported by data from the -Blocker Evaluation of Survival (BEST) Trial, in which the unique -blocker/sympatholytic agent bucindolol increased mortality in 14% of the treated population through a pronounced sympatholytic effect that was not observed in placebo-treated patients.7 The BEST Trial was stopped for benefit in the majority of the study population examined (non-black New York Heart Association Class III), with the degree of mortality reduction consistent with the results of other large -blocker trials just reported in these populations.8,9 In addition, in the entire BEST cohort, nearly all secondary end points were favorably affected by bucindolol.8 Dilution of efficacy to a statistically insignificant reduction (by 10%) in mortality in the larger cohort of BEST was due to the lack of efficacy in Class IV and black patients,8,9 which