Effect of Baseline or Changes in Adrenergic Activity on Clinical Outcomes in the β-Blocker Evaluation of Survival Trial

Abstract

Background-Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. Methods and Results-Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the ␤-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the ␤-blocker/ sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (PϽ0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization.In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. Conclusions-In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation ␤-blocker.

Reduction of Sympathetic Activity via Adrenal-targeted GRK2 Gene Deletion Attenuates Heart Failure Progression and Improves Cardiac Function after Myocardial Infarction

“…Nevertheless, even slight reductions in the catecholaminergic burden of the failing heart can have profound beneficial effects on cardiac function and overall clinical status of the HF patient (27). In fact, excessive plasma CA reduction has been postulated to actually be deleterious rather than beneficial in HF patients (27,28). Thus, it is absolutely plausible that the reductions in circulating CAs we observed in the PNMT-driven GRK2 KO mice can significantly impact cardiac function and ␤AR signaling post-MI in a beneficial manner.…”

“…Of note, the beneficial effects of adrenal-specific GRK2 deletion also include down-regulation of cardiac GRK2, an important indicator of cardiac dysfunction in HF, and are evident even without a dramatic reduction in CA levels, which could be detrimental for cardiac hemodynamic support of the circulation and incompatible with life (27,28). Thus, reduction of sympathetic activity/outflow via adrenal GRK2 inhibition as early as possible in the course of post-MI HF progression emerges as an attractive therapeutic strategy in the management of LV dysfunction.…”

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

“…A second clinical implication of our results is that the neurohormonal paradigm of sympathetic toxicity in heart failure should be reassessed. Indeed, adverse outcomes with doxazosin in ALLHAT and with NE reduction in the Moxonidine Safety and Efficacy (MOXSE) trial, the Moxonidine Congestive Heart Failure (MOXCON) trial, and the Beta-Blocker Evaluation of Survival Trial (BEST) (40)(41)(42) have raised concerns about …”

Sympathetic Overdrive and Cardiovascular Risk in the Metabolic Syndrome

“…This has been shown, for example, in patients with congestive heart failure, in which indirect and direct markers of systemic and regional sympathetic drive (venous plasma norepinephrine, heart rate variability, heart rate spectral power, cardiac and renal norepinephrine spillover) have been documented to bear a close and direct relationship with cardiovascular mortality, disease progression and arrhythmic events, including sudden death (46)(47)(48)(49)(50)(51). Similar conclusions have been drawn by assessing the prognostic values of plasma norepinephrine or heart rate variability in the post-stroke phase following an acute myocardial infarction or in patients with vasospastic angina (52)(53)(54)(55).…”