Novel Mechanisms of Sympathetic Regulation in Chronic Heart Failure

Abstract

The idea that activation of the sympathetic nervous system is part and parcel of the apparent positive feedback cycle of cardiac deterioration in the setting of chronic heart failure (CHF) is not a new one. Several reviews have clearly summarized the evidence for this concept using both clinical data and information from experimental models.1–4 Evidence from both neural recordings and measurement of circulating catecholamines clearly document a central origin for much of the sympathetic activation in CHF.5–7 Furthermore, the fact that sympathoinhibitory reflexes are depressed in CHF has been well established in humans8,9 and experimental animals.10–12 It has been suggested that abnormal arterial baroreflex function is largely responsible for sympathetic activation in CHF.13 However, experimental evidence in sino-aortic denervated dogs has challenged that concept.14 On the other hand, recent data from this laboratory has shown that depression of arterial baroreflex function is an early phenomenon in conscious rabbits during the development of pacing-induced CHF.15 In the past several years, the concept has emerged that, in addition to the depressed baroreflex, an increase in the sensitivity of several sympathoexcitatory reflexes also contribute to the sympathetic activation in CHF.16–19 Enhanced input from peripheral chemoreceptors16,20 and from receptors in the heart that traverse sympathetic pathways21 may provide for a positive feedback mechanism that exacerbates the sympathoexcitatory process, although in humans this issue is less clear.22 Activation of and enhancement in the sensitivity of these latter reflexes are attributable, in part, to changes in the interstitial milieu in which the afferents reside. Alterations in the local production of substances such as bradykinin, NO, prostaglandins, and so forth, have all been implicated as excitatory substances for cardiac and chemoreceptor afferents23–29 in heart failure. Because it is generally well accepted that the above reflexes …