The RAAS is predominantly a circulatory system, in which blood levels of the hormone exert direct effects on its target organs. The mediator of sympathetic nervous system (SNS ) activity, predominantly norepinephrine, is released at adrenergic nerve endings and exerts its effect locally. Thus, circulating levels of the hormone, although a reflection of release at the nerve endings, do not provide accurate insight into the degree of local activation [29, 30]. Nonetheless, elevated circulating levels of norepinephrine correlate directly with the severity of heart failure and with shortened survival times [3].

The mechanism or mechanisms by which heart failure leads to sympathetic nervous system activation are not well understood. Reduced stroke volume or reduced rate of pressure rise in the aorta may influence baroreceptors and induce sympathetic activation (◘ Fig. 16.2). Such a response to what may be perceived by the body as a reduction in arterial blood volume would appear to be an appropriate compensatory effort. Heart rate increases, myocardial contractility is augmented, the arterial system constricts to support blood pressure, and renal blood flow falls to inhibit volume loss. Traditionally, this sympathetic activation was believed critical in maintaining circulatory function in the setting of heart failure, but data in more recent years suggest that inhibition of the sympathetic nervous system response exerts a favorable effect on long-term prognosis in patients with heart failure [22–27], although some concern over its safety persists [31].

But a fundamental difference exists between the circulatory impact of activation of the RAAS and that of the SNS. RAAS stimulation activates angiotensin that exerts its effects on all circulatory beds. In contrast, SNS activation—through neural pathways and the release of norepinephrine—activates organ-specific receptors that exert quite distinctive effects. The most important of these are the alpha receptors that constrict the vascular smooth muscle and the beta receptors that stimulate the heart to increase its rate and its force of contraction [32]. These receptors respond independently to pharmacologic blockade [33].

Until the 1990s, the enhanced cardiac stimulation of beta receptors in heart failure was believed critical in maintaining cardiac output and perfusion of vital organs. When long-term trials with beta blockers, given in gradually escalating doses to minimize adverse effects on cardiac function, were shown to prolong life, it became apparent that cardiac stimulation was accompanied by progressive structural remodeling of the heart that shortened life expectancy [34, 35]. These drugs then began the transition from “contraindicated” to “mandated” therapy for heart failure with a dilated left ventricle [28].

The role of alpha receptor stimulation in heart failure remains more controversial. One would expect that alpha blockade to relax vasoconstriction, which impedes cardiac output in heart failure with a dilated ventricle, would be beneficial. Nonetheless, the vasodilator effect of alpha blockade does not appear to exert as much benefit on morbidity and mortality as does comparable vasodilation induced by drugs that activate nitric oxide (NO) [36]. Thus, alpha blockade is not advocated to enhance arterial dilation in heart failure. Furthermore, central inhibitions of the SNS by drugs that inhibit SNS activation have not improved outcomes [31, 37]. Consequently, the overall impact of sympathetic stimulation on the course of heart failure is uncertain.

Similar dysfunction of the left ventricle may occur in the presence of two rather distinct structural changes in heart failure (◘ Fig. 16.3). In heart failure with a dilated ventricle (HFDV) —often referred to as heart failure with a reduced ejection fraction (HFrEF) —the chamber is dilated, the wall sometimes thickened, the myocardial mass increased, and the wall motion greatly reduced. This pattern is common in patients who have suffered a prior myocardial infarction and also in patients with cardiomyopathy from nonischemic origins. The dilated chamber results from lengthening of myocytes as a result of new sarcomere growth longitudinally in series in the myocytes [38].

In heart failure with a non-dilated ventricle (HFNDV)—often referred to as heart failure with a preserved ejection fraction (HFpEF)—the chamber is not enlarged, but the wall is usually thickened. This pattern is commonly observed in elderly individuals, often women, and generally has a better prognosis than the dilated ventricle syndrome [39]. The sarcomere growth pattern in this syndrome thickens the myocyte because of sarcomere growth in parallel.

Neurohormonal activation occurs in both structural syndromes of heart failure, but the magnitude of activation is generally greater in the HFDV syndrome. Indeed, large-scale prospective studies have demonstrated the effectiveness of neurohormonal-inhibiting therapy with HFDV syndrome [22–27]. Attempts to document benefit of such therapy in the HFNDV syndrome have generally been disappointing [40–42]. These contrasting experiences have strengthened the hypothesis that the major therapeutic benefit of neurohormonal blocking therapy in heart failure is its inhibiting effect on the cardiac remodeling that contributes to chamber dilation (◘ Fig. 16.1).

Treatment goals for symptomatic heart failure are twofold: (1) relieve the symptoms of heart failure and improve quality of life and (2) prolong life. Until the 1980s, managing chronic heart failure was limited to digitalis to enhance contraction of the failing left ventricle and diuretics to relieve the circulatory congestion that was manifested as shortness of breath and edema. Recognizing that vasoconstriction was placing a reversible impedance load on ventricular emptying, and that neural and hormonal stimulation was contributing to both vasoconstriction and adverse cardiac remodeling, led to the current universal recommendation that patients with heart failure associated with a reduced ejection fraction (HFrEF) —or HFDV —should be treated with one, two, or perhaps all of the following drugs: an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-adrenoceptor blocker, and an aldosterone inhibitor [28] (◘ Fig. 16.4). Multiple large-scale trials have shown reduced mean morbidity and/or mortality when the effect of each of these drugs is compared to comparable patients managed without each of these drugs [22–27].

It is important to understand what these large-scale trials demonstrating efficacy mean for individual patients. They do not imply that all individuals with the disease process will benefit from the drug in question. Differing genetic and environmental factors render each individual and their disease process unique. In the population of individuals studied, the trial results imply that the benefit of randomized assignment to the study medication exerted greater benefit than harm on the end point selected for study. Some individuals may have been harmed, but more individuals in the population were benefited. All trials assess benefit in populations, not necessarily in individuals.

Given that caveat, guidelines use these large-scale trials as the basis for recommending treatment regimens for patients with heart failure, at least those having the baseline characteristics of those included in the trials. These recommendations probably do not apply to all individuals who meet the criteria, but in the absence of clear evidence for excluding specific individuals, the recommendations have come to be applied to all. The following analysis provides the mechanistic and trial basis for the currently recommended drug management of chronic heart failure. Unless otherwise stated, these recommendations are confined to patients with chronic, stable heart failure accompanied by a dilated left ventricle with a reduced ejection fraction .

The renin-angiotensin system is stimulated early in the heart failure syndrome, presumably as a change in renal sodium handling. Since angiotensin constricts the arterial microcirculation and stimulates vascular smooth muscle growth, its inhibition improves left ventricular emptying and modestly enhances cardiac output [43] (◘ Fig. 16.5). Furthermore, despite angiotensin’s minimal effect on venous constriction, drugs that interfere with angiotensin action also reduce venous pressure. Elevated venous pressure contributes to shortness of breath and edema. It remains unclear how much of this venous effect is contributed by bradykinin stimulation and how much by sympathetic inhibition, which also may be mediated by angiotensin inhibition. Nonetheless, angiotensin inhibition improves the hemodynamics in heart failure, thus relieving symptoms and improving quality of life. Furthermore, because of angiotensin’s role in stimulating both cardiac and vascular smooth muscle growth, its inhibition is accompanied by a reduced rate of left ventricular remodeling and improved long-term prognosis [11, 25].

The benefits of angiotensin inhibition can be gained with either an ACE inhibitor or an angiotensin receptor blocker. The sequence of their development led most ACE inhibitor trials to compare the various agents to placebo, where they were effective in reducing morbidity and mortality. In later ARB trials, however, the drugs were compared largely as additive to ACE inhibitors , where modest morbidity reductions could be shown but not necessarily a further reduction in deaths.

Important pharmacologic differences exist in the response to these two classes of drugs. ACE inhibitors reduce angiotensin II levels, at least transiently, and stimulate bradykinin. ARBs selectively block AT1 receptors but result in an increase in angiotensin II levels, thus potentially enhancing AT2 receptor-mediated responses. How these pharmacologic differences influence the short-term and long-term effects of these drugs is largely unknown.

Dosing of these angiotensin-inhibiting agents has traditionally been based on the response, that is, reduced blood pressure in managing hypertension. In heart failure, however, dosage has been based on the target doses achieved in long-term outcome studies. It has been suggested that dosing in hypertension should similarly be aimed at target doses rather than target responses [44]. Tolerability to these target doses is documented by gradual escalation of the dose. A dangerous reduction in blood pressure, or intolerable dizziness when standing, mandates reduction in the dose of these drugs. A modest rise in serum creatinine is a common observation when initiating therapy, but this azotemia is usually reversible and should not require dose reduction unless it becomes progressive.

It is likely that the benefits of ACE inhibitors and ARBs in managing heart failure represent a class effect of these drugs and likely apply to all members of the class. Drug marketing restrictions mandate, however, that only drugs that have undergone adequate controlled studies in heart failure can be labeled for use in that syndrome. Furthermore, specific dosing recommendations for any drug would depend on a clinical trial demonstrating efficacy of that target dose. With ARBs, there is little reason to suspect that individual drugs in that class exert a different spectrum of effects . With ACE inhibitors , however, differing effects may relate to tissue penetration. Some lipophilic agents may more effectively gain access to tissue compartments where the local renin-angiotensin system may be activated. Whether such local effects are of importance in the response to ACE inhibitors in heart failure is uncertain.

Historically, the clinical benefit of beta blockers to treat heart failure was documented after ACE inhibitors became standard therapy. Their use, therefore, is generally recommended to supplement inhibitors of angiotensin effect. Furthermore, since beta blockers do not produce short-term improvement in hemodynamics nor short-term benefit in quality of life, their dosing requires gradual escalation to avoid adverse effects. Background angiotensin-inhibiting therapy probably enhances tolerability of the beta blockade. Thus, the general recommendation of initiating ACE inhibitor or ARB therapy first, and then initiating a beta blocker regimen, is rational.

Beta blockers’ main site of action in heart failure is on inhibiting the left ventricular myocyte and collagen remodeling process (◘ Fig. 16.5). This effect is associated with reduced ventricular volume and improved ejection fraction [25–27]. Thus, it is important to confine this pharmacologic approach to patients with dilated ventricles and a reduced ejection fraction.

The mechanism by which beta blockade inhibits remodeling remains controversial. If it relates exclusively to inhibition of the sympathetic nervous system, it is unclear why the benefits are not replicated by central sympathetic nervous system inhibition by drugs such as clonidine and moxonidine [31, 37]. Since a similar benefit on remodeling and outcome is associated with the use of ivabradine, a drug that slows heart rate without inhibiting the sympathetic nervous system [45], one hypothesis is that the benefit of beta blockers is mediated primarily through cardiac slowing .

Although the beneficial effect of beta blockers in heart failure is viewed largely as an effect of this class of drugs, individual differences in the mechanism and site of action of beta blockers make it problematic to use agents that have not been adequately tested in this syndrome. Beta-1 selectivity and other pharmacologic properties of individual drugs vary widely and may impact their effectiveness in heart failure .