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 short-term 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 …