The clinician has long been aware that heart failure begets heart failure ; that is,in patients with heart failure associated with left ventricular (LV) systolic dysfunction,the clinical syndrome is known to worsen spontaneously over time.In animal models and in humans with myocardial injury,progressive hypertrophy,dilatation and remodeling of the left ventricle have been observed,and the pathogenesis of these changes has become the subject of extensive investigation.In parallel with this work,we have come to recognize the importance of neurohormonal activation in patients with LV systolic dysfunction. A variety of neurohormonal systems are up-regulated in this condition,including the adrenergic nervous system,the renin-angiotensin system,and a system of vasodilator peptides of cardiac origin. Although originally thought to effect their actions through systemic vasoactive effects, it is now well known that paracrine and antocrine actions are also operative. For example, the various components of the renin-an giotensin system are present in multiple tissues, including the vasculature and the cells of the myocardium : myocytes, fibroblasts, myo-fibroblasts, and endothelial cells. The clinical relevance of these concepts is enormous. Angiotensin converting enzyme inhibitors are likely to mediate their beneficial effects on clinical outcomes through both systemic vasoactive and local tissue effects. Evidence is increasing for the clinical benefit of beta adrenergic blockade. Agents which stimulate these neurohormonal systems, such as some calcium channel blockers, are known to accelerate the progression to clinical heart failure and mortality. A growing body of literature supports a potential benefit of certain newer dihydropyridine calcium channel blockers, which may be linked to lesser or absent neurohormonal activation by these agents. Understanding the physiologic, cellular, and molecular bases of adverse myocardial hypertrophy and remodeling is likely to lead to major new advances in the prevention and management of heart failure and ventricular dysfunction.

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It has long been recognized that congestive heart failure is characterized by a neurohumoral excitatory state leading to systemic vasoconstriction and salt and water retention.The most prominent aspect of this neurohumoral excitation is the striking increase in sympathetic nerve activity and plasma norepinephrine levels which occur and which worsen as the heart failure progresses. At the same time that this sympatho-excitation occurs, the reflexes which normally restrain sympathetic nerve activity and augment vagal drive to the sinus node become impaired. For a number of years there has been a working hypothesis that these two abnormalities, i.e., reflex abnormalities and sympatho-excitation, are causally related. Moreover, treatment of heart failure with medications (such as with cardiac glycosides) or by cardiac transplantation results in reversal of both the neurohumoral excitatory state and improvement in or normalization of cardiovascular reflexes. In order for impairment in sympatho-inhibitory reflexes to lead to the development of the sympatho-excitatory state, such reflex abnormalities must precede the development of neurohumoral excitation. The development of animal models such as the canine rapid ventricular pacing model indicate that reflex abnormalities precede the development of neurohumoral excitation. Such results indicate a potential causal role for reflex abnormalities leading to sympatho-excitation and inhibition of vagal influences in heart failure, but do not establish a cause and effect relationship. A portion of this manuscript will focus on neurohumoral and cardiovascular reflex abnormalities and their potential causal relationship during the development of left ventricular dysfunction and its progression to clinical heart failure.
Although it's certainly possible that impairment of cardiovascular reflexes leads to sympatho-excitation and vagolysis, it's also possible that neurohumoral excitation precedes and/or contributes to the development of abnormal reflexes in some models of heart failure, including in humans. Recent studies from our laboratoty suggest that interruption of components of the neurohumoral excitatory state, particularly of the renin-angiotensinaldosterone axis, leads to improvement in cardiovascular reflex responses. Thus, administration of angiotensin-converting enzyme inhibitor appears to improve the sensitivity of arterial and cardiopulmonary baroreflexes and inhibit sympathetic nerve activity. Such improvement is not evident when there is left ventricular dysfunction without neurohumoral excitation. The relative contribution of reflex impairment to neurohumoral excitation versus reflex abnormalities resulting from neurohumoral excitation remains to be investigated in such a way as to help us to understand the most fundamental aspects of their relationships.
In this review, we will focus on abnormalities of arterial baroreflexes and of vagal cardiopulmonary baroreflexes and their relationship to neurohumoral excitation in heart failure, and the effects of therapy on both reflexes and neurohumoral mechanisms.Potential causal relationships will be discussed.

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