Introduction
Chronic heart failure has long been recognized as a cause of considerable mortality and morbidity in adults. The early recognition of heart failure in the 17th and 18th centuries was that of edema, anasarca, and dyspnea, which was appropriately attributed to blood “backing up” behind an impaired pump, the heart. Early descriptions of heart failure in children were usually in the setting of rheumatic fever. It was not until 1936 that Abbott mentioned “isolated” cardiac insufficiency as a cause of death in children, although we now recognize that chronic heart failure and cardiomyopathy are indeed important causes of morbidity and mortality in children. Among children with cardiomyopathy who entered a national population-based registry in Australia between 1987 and 1996, freedom from either transplant or death at 5 years after diagnosis was only 83% for those with the hypertrophic and 63% for those with the dilated form of the disease.
The concepts that underlie our understanding of chronic heart failure in both children and adults have changed considerably in recent years. This chapter summarizes some current concepts related to key pathophysiologic processes in chronic heart failure and examines the outcomes of its treatment.
Basic Concepts in Chronic Heart Failure
Although, for centuries, heart failure was considered to be the result of a severe and irreversible injury to the heart leading to an irremediable abnormality of the ventricle’s systolic function, it is now recognized that the syndrome of heart failure reflects a more complex, dynamic, and progressive process that can no longer be defined in simple hemodynamic terms and that affects not only on the heart itself but also a myriad of extracardiac physiologic processes.
The current framework considers heart failure―whether due to ischemia, infection, altered cardiac load, or tachycardia―to be a condition in which a primary insult to the heart results in a cascade of secondary responses affecting the heart as well as related organs. It appears that irrespective of the precise nature of the primary insult, for the most part the secondary responses and clinical evolution share common features, so that the progression of heart failure represents an ordered, predictable, coordinated cascade of events. Although this may initially be reversible, it can, in the absence of treatment, result in terminal heart failure and ultimately death.
These secondary responses to cardiac injury may, at least in the initial phase, be adaptive and designed to preserve the flow of blood to the vital organs. Thus, in response to a regional injury of the myocardium, global function is maintained by invoking a number of compensatory mechanisms. The regional function of the uninjured myocardium increases and the ventricle hypertrophies as growth factors within the myocyte accelerate the synthesis of protein and growth of the myocyte. As described later, a reduction in perfusion pressure within the kidneys is detected by receptors in the renal arterioles, activating the complex renin-angiotensin-aldosterone system to cause constriction of the efferent arterioles so that the glomerular filtration pressure is maintained along with a balance of salt and water. Increased activation of the neuroendocrine system, manifest by the systemic release of neurohormones such as noradrenaline and adrenaline, maintains cardiac output through chronotropic and inotropic activity.
With time, these mechanisms become maladaptive as the patient progresses into a phase of decompensated heart failure. The increase in left ventricular mass together with dilation of the ventricle augments mural stress within the myocardium and its consumption of oxygen, potentially worsening the myocardial injury. Chronic activation of the renin-angiotensin system results in edema, the elevation of pulmonary arterial pressure, and increased afterload. Sympathetic activation increases the risk of arrhythmia and sudden death. Although these changes may be reversed by successful treatment, it has been suggested that such treatment must be initiated before the patient reaches the so-called terminal threshold, after which recovery of left ventricular function is not possible ( Fig. 65.1 ).
Function of the Normal and the Failing Heart
The ability to accurately describe the function of the heart, its metabolic demands and its interactions with the vasculature, is of paramount importance in analyzing the mechanisms of circulatory failure and the effects of interventions in patients with myocardial disease. In clinical practice our assessment of cardiac function is usually limited to the indirect estimation of ventricular systolic and end-diastolic pressure, ejection fraction, and, in some echocardiography laboratories, the assessment of mural stress. However, a complete evaluation of cardiac function would extend further, ideally to include an indicator of ventricular systolic and diastolic performance that is relatively independent of load, an assessment of the myocardial consumption of oxygen, and an examination of the relationship between ventricular performance and cardiac load.
Since Suga presented his analysis of the instantaneous pressure-volume relationship and subsequently developed the concept of time-varying elastance, there has been heightened interest in the use of the pressure-volume relationship in assessing ventricular performance. This has been especially true in recent years with the introduction of the conductance catheter technique, which allows high-fidelity online measurements of ventricular pressure and volume at fast acquisition speeds.
The classic work of Wiggers, which describes changes in left ventricular pressure and volume during the cardiac cycle, has provided the foundations for our current understanding of ventricular function. In Wiggers’ schema, the cardiac cycle begins with the onset of depolarization on the electrocardiogram, which is soon followed by an increase in pressure within the ventricle. When left ventricular pressure exceeds left atrial pressure, the mitral valve closes. The aortic valve remains closed while aortic pressure still exceeds left ventricular pressure, and ventricular volume therefore remains constant; so-called isovolumic contraction exists. When left ventricular pressure exceeds aortic diastolic pressure, the aortic valve opens and the ventricle begins to eject. Consequently the volume of the left ventricle falls ( Fig. 65.2 ).
Diastole is traditionally assumed to begin with closure of the aortic valve; however, the decay in ventricular pressure (relaxation) begins before this event. After aortic valve closure, ventricular pressure continues to decay rapidly―an energy-requiring mechanism―together with the passive release of myocardial elastic forces generated during contraction. As the ventricular pressure continues to decay, the mitral valve initially remains closed. The period of relaxation during which ventricular volume remains constant is termed isovolumic relaxation.
When ventricular pressure falls below atrial pressure, the mitral valve opens and ventricular filling begins. During the early period of ventricular filling, the ventricle’s pressure falls. This anomalous relationship between pressure and volume is thought to result from restorative forces, which attempt to restore the shape of the ventricle to that at end-diastole. After this time, both pressure and volume increase in the ventricle, which exhibits elastic behavior. Later in diastole the rate of ventricular filling is further augmented by atrial contraction.
Examination of Cardiac Function With the Pressure-Volume Loop
Up to this point, we have considered the temporal changes in left ventricular pressure and volume; however, the essence of the pressure-volume analysis is to consider the relationship between ventricular pressure and volume, represented by the pressure-volume loop. The latter has four characteristic phases. Beginning at the bottom right hand corner (I to II in Fig. 65.2 ), an initial upstroke represents the rapid increase in ventricular pressure, with little volume change; this is isovolumic contraction. There is then a rapid fall in ventricular volume as ventricular ejection proceeds to the end-systolic point (II to III). Ventricular pressure then rapidly falls, with little volume change, as the ventricle enters the isovolumic relaxation phase (III to IV). Finally, ventricular volume increases to its end-diastolic level, reflecting ventricular filling (IV to I).
Suga noted that at a constant inotropic state, alterations in ventricular load resulted in a population of pressure-volume loops in which, at any time in the cardiac cycle, the pressure-volume points follow a straight line. It was proposed, therefore, that cardiac contraction could be modeled as a time-varying elastance, with maximal elastance occurring at end-systole (end-systolic elastance), represented by the upper left-hand corner of the pressure-volume loop ( Fig. 65.3 ).
While the end-systolic pressure-volume relationship has been considered the definitive measure of ventricular contractility, the importance of other indices should not be underestimated. It is important to emphasize that there is no single gold-standard measure, which will encompass the complex physiologic processes that determine myocardial contractility, rather, there are a number of measures, each of which provides individual pieces of a complex jigsaw.
It must be appreciated that the pressure-volume relationship provides a wealth of information about cardiovascular physiology beyond end-systolic elastance. The intricate coupling between the ventricle and the vasculature is an extremely important clinical determinant of cardiovascular function. Although many treatments for heart failure are aimed at augmenting ventricular systolic performance, it is clear that without the ability of the vasculature to convert within itself the increased pressure work of the ventricle into flow work, these therapeutic strategies would be of little benefit. One measure of the efficiency of ventriculovascular coupling, based on an examination of the pressure-volume relationship, examines the coupling between end-systolic elastance and arterial elastance to illustrate how the arterial response determines the physiologic effect of an increase in contractility during inotropic stimulation.
The pressure-volume relationship can also provide important information regarding the energetic state of the ventricle. In many critically ill patients with myocardial disease, the relationship between myocardial oxygen demand and supply is already precarious; it is therefore imperative that any potentially desirable augmentation of ventricular performance should not be offset by adverse effects on myocardial metabolism and energetics. Suga demonstrated that the total energy consumption of the ventricle can be quantified by the specific area in the pressure-volume diagram that is bounded by the end-systolic and end-diastolic pressure-volume relations and the systolic pressure-volume trajectory. The scope of the pressure-volume diagram therefore extends beyond cardiac mechanics to include cardiac energetics and mechanoenergetic coupling under varying contractile conditions.
The use of the pressure-volume relationship to assess the diastolic properties of the ventricle is based on the assumption that throughout the period during diastole when both volume and pressure are increasing, the ventricle exhibits elastic behavior. As a result, at any point during this time, the slope of the relationship between pressure and volume represents ventricular compliance. As the normal pressure-volume relation at this time is curvilinear, chamber compliance becomes lower as filling proceeds, indicating that the cavity has become stiffer. The pressure-volume curve during this part of diastole is usually assumed to be exponential and to show behavior characteristic of Lagrangian stress, so that, if pressure is plotted logarithmically and volume linearly, then a linear relationship will be obtained; it is then possible to calculate its slope and intercept.
There are few data addressing the changes that occur in the ventricular pressure-volume relationship in children with myocardial failure. However, studies in adults have shown that assessment of the pressure-volume relationship can be used to determine the effects of progressive myocardial failure on integrated cardiovascular performance.
Studies investigating the matching of ventricular properties to arterial load are particularly important in this respect. In normal subjects with an ejection fraction of 60% or more, ventricular elastance is nearly double arterial elastance. This condition affords an optimal coupling between ventricular work and oxygen consumption. In patients with moderate heart failure and ejection fractions of 40% to 59%, ventricular elastance is almost equal to arterial elastance, a condition affording maximal stroke work from a given end-diastolic volume. However, in patients with severe heart failure, with ejection fraction of less than 40%, ventricular elastance is less than half of arterial elastance, which provides a suboptimal relationship between ventricular work and either oxygen consumption or stroke volume. These studies suggest that ventriculoarterial coupling is normally set toward maximizing work efficiency in terms of the relationship between left ventricular work and oxygen consumption. As heart function becomes impaired in patients with moderate cardiac dysfunction, ventricular and arterial properties are initially matched in order to maximize stroke work at the expense of work efficiency. However, as cardiac dysfunction becomes severe, the ventricle and vasculature become uncoupled, so that neither the stroke work nor work efficiency are near maximum for patients with severe cardiac dysfunction.
Whereas up to this point we have considered the function of the left ventricle as a whole, regional dyssynchrony of left ventricular function is frequently observed in patients with heart failure, in whom it results in inefficiencies in the contraction of left ventricle, a decreased cardiac output, and increased risk of sudden cardiac death ( Fig. 65.4 ). Recently, new therapies aimed at restoring mechanical synchrony in such patients have been shown to result in improvements in symptoms and outcomes.
Cellular Physiology of the Cardiac Myocyte
Before discussing the cellular mechanisms associated with the development of myocardial failure, it is necessary to examine the structure and function of the normal cardiomyocyte. This section examines some of the principles related to this topic, although it will not provide a comprehensive review of the multitude of intracellular and intercellular messengers; these have been considered in some excellent specialist reviews. Cardiac myofibers are composed of groups of muscle cells (cardiac myocytes) connected in series and surrounded by connective tissue. Each cardiomyocyte is bounded by a thin bilayer of lipid (the sarcolemma) and contains bundles of myofibrils arranged along its long axis. These myofibrils, in turn, are formed of repeating sarcomeres, the basic contractile units of the cell, composed of thick and thin filaments, which provide the myocyte with its characteristic striated pattern. The thick filaments consist of interdigitating molecules of myosin and the myosin-binding proteins, while the thin filaments consist of monomers of α-actin as well as the regulatory proteins α-tropomyosin and troponins T, I, and C. A third filament within the myofibril is the giant protein titin.
Cardiac myocytes are joined at each end to adjacent myocytes at the intercalated disc. This disc contains gap junctions (containing connexins) that mediate electrical conduction between cells and mechanical junctions, composed of adherens junctions and desmosomes. The myocyte also contains an extensive and complex network of proteins linking the sarcomere with the sarcolemma and, in turn, with the extracellular matrix. This highly organized cytoskeleton provides support for subcellular structures and transmits mechanical and chemical signals within and between cells by activating phosphorylation cascades.
Myocardial activation is dependent on excitation-contraction coupling. This is mediated through the release of calcium into the myocyte from the extracellular space but more importantly from intracellular stores, particularly from an intracellular network of membranes, the sarcoplasmic reticulum. It appears that the generation of an action potential facilitates the influx of calcium from the extracellular space through the so-called L-type calcium channels, which are particularly concentrated in specialized areas of the sarcolemma (transverse tubules) and invaginate into the cell to reach its interior, close to receptors on the surface of the sarcoplasmic reticulum (the so-called ryanodine receptors). The increase in the intracellular concentration of calcium, which results from its influx from the extracellular space, triggers further release of calcium from the sarcoplasmic reticulum. The calcium activates myocardial contraction through its interaction with regulatory proteins on the myofibrils. Conversely, diastole is heralded by the reuptake of calcium into the sarcoplasmic reticulum through the activation of an energy-dependent mechanism residing with the so-called sarcoplasmic reticulum calcium ATPase, which itself is regulated by a number of stimulatory and inhibitory proteins, in particular the inhibitory protein phospholamban.
The ambient level of myocardial activation is modulated by the actions of catecholamines through their interaction with specific receptors on the surface on the myocyte. Stimulation of these receptors invokes a series of complex intracellular phosphorylation cascades that modulate not only the rate of influx of calcium from the extracellular space but also the release and reuptake of calcium from the sarcoplasmic reticulum and the affinity of the myofibrillar proteins for calcium.
Central to the function and homeostasis of the cardiomyocyte is the mitochondrion. As the heart is the organ in the body with the highest rate of oxygen uptake and an enormous demand for the continuous synthesis of adenosine triphosphate by oxidative phosphorylation, cardiac myocytes have a very high density of mitochondria. This central role for the mitochondrion as the power source for the cell and its position as the major site for the transformation of energy within the myocyte has been well established. Energy is stored in the form of high-energy phosphate bonds in adenosine triphosphate. The free energy necessary for the formation of the adenosine triphosphate by the phosphorylation of adenosine diphosphate is derived from the oxidation of nicotinamide adenine dinucleotide by the electron transport chain.
In addition to playing a central role in the metabolism of oxygen, it is now recognized that the mitochondrion plays a crucial role in both apoptosis and necrosis through its so-called permeability transition pores. The mitochondrion contains all the necessary machinery for apoptosis and is now acknowledged to be a key determinant of whether a myocyte will live or die after a pathologic insult. Central to this determination is the role of reactive oxygen species, generated by the diversion of electrons from the electron transport chain. Although it has long been established that excessive levels of superoxide may result in damage to biologic molecules―for example the sarcolemma and intracellular proteins―it is also established that reactive oxygen species play a central signaling role within the cell, which may not only regulate the key metabolic pathways within the cell but also prevent apoptosis and cellular necrosis. It is clear, therefore, that the mitochondrion and reactive oxygen species play a central role as executioner or savior in determining the viability of the cardiomyocyte.
Cardiac Myocyte in Heart Failure
Having considered the basic physiology of the cardiac myocyte, it is of interest to consider that any of these elements―the myofibrils, the sarcolemma, the gap junctions, the cytoskeleton, the mechanism of excitation-contraction coupling, the adrenergic receptors, or the mitochondria―may contribute to the pathogenesis of heart failure. This role may be a primary one; for example, the abnormality of the mitochondrion seen in a patient with a so-called mitochondrial cardiomyopathy ; the abnormality of the key component of the cytoskeleton, dystrophin, in the patient with muscular dystrophy ; or the mutation in a sarcomeric protein in a patient with hypertrophic cardiomyopathy. Abnormalities of these elements may also occur secondary to a primary insult originating outside the myocyte. They may thus represent the final common pathway in the development of heart failure and the maladaptive myocardial response to a host of primary external insults. Thus the development of heart failure secondary to ischemia-reperfusion injury may be associated with abnormalities of the myocardial mitochondrion in association with alterations in the expression and function of the adrenergic receptors. In patients with viral myocarditis, changes in the function of the mitochondrion may herald the onset of apoptosis, whereas enteroviral proteases may cleave dystrophin, leading to a secondary impairment of the mitochondrion’s function.
Other Organs and Mediators in Chronic Heart Failure
It is now clear that the syndrome of heart failure is a multisystem disease, affecting not only the heart but also many other organs and processes including the sympathetic nervous system, the kidney, the gastrointestinal system and nutrition, hemopoiesis, the brain, and skeletal muscle. Of these only a few will be considered here.
Sympathetic Nervous System
It is now widely acknowledged that activation of the sympathetic nervous system plays a central role in the pathogenesis of congestive heart failure. This activation occurs early in the course of the disease, even before the onset of symptoms, and as the syndrome evolves may play both adaptive and maladaptive roles. It appears that in the early stages of the syndrome, before the onset of symptoms, activation of the sympathetic nervous system occurs selectively within the heart and kidneys. It has been suggested that this initially selective activation occurs secondary to ventricular dilation, which stimulates the release of natriuretic peptides and activation of the cardiac sympathetic nervous system. This initially adaptive response to ventricular dysfunction may preserve myocardial function. However, with worsening heart failure as cardiac output and systemic blood pressure fall, this selective activation of the sympathetic nervous system becomes generalized as the high-pressure baroreceptors within the heart and the carotid sinus become unloaded.
Although activation of the sympathetic nervous system may play an important role in maintaining cardiac output and arterial blood pressure in the early stages of the condition (adaptive response), with time catecholamines may have detrimental effects. Elevated levels of catecholamines in the plasma have been shown to correlate with decreased survival; this may be secondary to myocardial hypertrophy or activation of the renin-angiotensin system. Catecholamines are also known to be toxic to the myocyte through their effects on the intracellular levels of calcium.
Retention of Sodium and Water
From the time that the condition was known as dropsy, retention of salt and water has been recognized to be a prominent feature of heart failure. Recent decades have considerably improved our understanding of the mechanisms responsible for the retention of sodium and water and in particular have highlighted the contributions of activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the role of arginine vasopressin, aquaporins, and the natriuretic peptide systems.
A pivotal trigger in the development of sodium and water retention has been posited to be arterial underfilling secondary to a reduction in cardiac output. Unloading of the baroreceptors in the arterial tree results in the activation of sympathetic nervous activity, including effects on the kidneys, where it may not only directly cause the retention of sodium and water but also stimulate the renin-angiotensin system. Activation of the sympathetic nervous system within the supraoptic and paraventricular nuclei of the hypothalamus results in the release of vasopressin, which further contributes to the retention of water by the kidney.
Activation of the renin-angiotensin system occurs early in the evolution of heart failure, with levels of renin within the plasma being observed before the onset of symptoms in patients with subclinical ventricular dysfunction. Angiotensin plays a number of roles in the pathogenesis of heart failure. Although its synthesis is stimulated by sympathetic stimulation, angiotensin, in turn, enhances activity of the sympathetic nervous system through a positive feedback loop. Angiotensin II has important vasoconstrictor properties as well as contributing directly to the development of cardiac hypertrophy and fibrosis. It plays a central role in retaining sodium and water through its direct effects on the tubular absorption of sodium as well as indirectly through its effects of the secretion of aldosterone by the adrenal gland.
The natriuretic peptide system, which is activated in heart failure, is also important in the retention of sodium and water. In normal subjects, natriuretic peptides increase the rate of glomerular filtration and sodium excretion by the kidney. Although the secretion of natriuretic peptides is increased in the early stages of the evolution of heart failure, it is now known that heart failure is associated with considerable resistance to their actions. This resistance to natriuretic peptides―which may contribute substantially to the retention of sodium―has been attributed to a number of factors including a downregulation of the receptors for natriuretic peptide in the kidney, the secretion of biologically inactive natriuretic peptide, or the enhanced degradation of natriuretic peptide by the enzyme neutral endopeptidase or by phosphodiesterase.
Although for decades it was thought that vasopressin contributed little to the retention of water in patients with heart failure, it has been shown more recently that vasopressin, through its actions on aquaporins within the collecting duct of the renal tubule, may play a central role. In animal models of congestive heart failure, the expression of aquaporin-2 is increased, and in clinical studies antagonists of vasopressin may result in a dose-related increase in water excretion.
Treatment of Chronic Heart Failure
The treatment of chronic heart failure has changed greatly over the years. Not surprisingly, once it was recognized that the cause of congestive heart failure was a failing pump, treatment strategies were directed toward making the pump work better. For centuries, the only treatment available for heart failure was digitalis. First described by Withering in his classic monograph in 1785, this author praised the efficacy of the leaves of the common foxglove plant. With the advent of the understanding of the complex neurohormonal syndrome now recognized as heart failure, strategies for the treatment of heart failure have changed from that of increasing pump function to that of decreasing the maladaptive neurohormonal stimulation associated with heart failure. In fact, no positive inotropic medication has been shown to increase survival in heart failure. The following discussion focuses on the current strategies for the treatment of heart failure, particularly as related to children. The development of an evidence base for the treatment of chronic heart failure is somewhat unique in that few drugs solely for the treatment of heart failure have been developed; angiotensin converting enzyme (ACE) inhibitors, β-adrenergic blockers, and adrenergic receptor blockers (ARBs) were developed initially for the treatment of hypertension.
The use of the term heart failure in children can have many different implications. Patients with large left-to-right intracardiac shunts with pulmonary overcirculation and tachypnea can be described as being in heart failure despite that fact that ventricular performance is usually normal. Surgical outcomes for the treatment of these types of lesions, even in the smallest and youngest of infants, are now good enough to recommend early surgical correction. Thus, with few exceptions, long-term medical management of these structural lesions is unnecessary and is not discussed in this chapter. Similarly, medical management of symptomatic valvar regurgitation is no longer routinely considered, since surgical correction is the treatment of choice in most cases. Finally, an evidence base is lacking for the treatment of patients with cardiac failure with preserved ejection fraction, particularly children. Because of this paucity of data, this type of heart failure is not discussed. The remainder of this chapter focuses on the treatment of heart failure with reduced ejection fraction (HFrEF) in children and adults.
Digoxin
As stated earlier, digitalis has been the mainstay of chronic heart failure treatment for centuries. Even before physicians knew what actually caused edema, shortness of breath, and/or anasarca, it was understood that digitalis improved these maladies in addition to normalizing an irregular heart rate. Once it was known that this syndrome of edema, shortness of breath, anasarca, and irregular heart rate was due to poor cardiac function, the use of digoxin as a treatment needed to be studied more carefully. The mechanism of action is through inhibition of the sodium-potassium pump both within the heart and elsewhere. Within the heart such inhibition results in increased contractility, while outside the heart it reduces the sympathetic outflow from the central nervous system and the release of renin by the kidney. Several studies have helped to define the role of digoxin in the treatment of heart failure, showing that, although digoxin does not improve survival, it may improve symptoms. Current recommendations in adults are that physicians consider adding digoxin in patients with persistent symptoms of heart failure during therapy with diuretics along with an ACE inhibitor or ARB and a β-adrenergic blocker. Toxicity from digoxin was common when serum levels exceeded 2.0 ng/mL; therefore the early practice was to maintain levels to just below toxicity to achieve maximal benefit. More recent retrospective analyses of this and other studies suggest that lower doses may be better than higher doses. There is now increasing evidence that lower levels of digoxin are safer and at least as efficacious as higher levels for the treatment of chronic heart failure. Since digoxin appears to be helpful only in the treatment of symptomatic heart failure, there is little if any role for it in the treatment of asymptomatic heart failure. In the most recent recommendations of the American Heart Association and the American College of Cardiology, digoxin is recommended only in the treatment of symptomatic HFrEF and is actually contraindicated in asymptomatic patients unless atrial fibrillation is present.
The indications for the use of digoxin in pediatric heart failure are less clear. The most recent recommendations of an expert group of pediatric cardiologists recognize that there are few data to support or refute its use in pediatric heart failure. In patients with left-to-right shunts such as ventricular septal defects, the data are conflicting as to whether digoxin has any beneficial hemodynamic effects. In one study, digoxin acutely worsened hemodynamics in children with heart failure due to left-to-right shunts. There are no data to either support or refute the use of digoxin in children with heart failure due to ventricular dysfunction. Thus, in the absence of pediatric data, one can consider using the recommendations for digoxin in adult HFrEF with the caveats that these extrapolations become much less justifiable in the extremely young child or in the child with systemic ventricular dysfunction whose systemic ventricle is not of a left ventricular morphology. Major side effects include arrhythmias and gastrointestinal and neurologic symptoms. Digoxin interacts with many medications (e.g., amiodarone, carvedilol, verapamil, spironolactone, flecainide, propafenone), and interactions should be explored before digoxin therapy is instituted.
Diuretics
Although diuretics have never been shown (and possibly never will be) to improve survival in heart failure, their use is considered important because of the need for anticongestive measures in the treatment of heart failure. This is based largely on the significant symptomatic relief and hemodynamic improvement seen in patients with congestive heart failure treated with diuretics. A large number of diuretics are available, including those that act on the renal loop of Henle (loop diuretics) and those that act in the distal tubules of the kidney (thiazides). Potassium-sparing diuretics are discussed in the later section on aldosterone antagonists. Diuretics interfere with the retention of sodium in the kidney, and water follows this increased excretion of sodium passively. This causes a decrease in filling pressure of the ventricle and a reduction in right-sided (e.g., hepatic) and left-sided (e.g. pulmonary) congestion. The most common side effects are depletion of electrolytes and fluid (e.g., hyponatremia, hypokalemia), elevated urea levels in the plasma, and even hypotension if excessive diuresis takes place. There is some evidence from retrospective analyses of previous trials that diuretics that do not result in the sparing of potassium may actually be harmful in the treatment of heart failure, but further prospective studies are needed to confirm this.
Inhibitors of the Renin-Angiotensin System
As stated earlier, the primary thrust of the treatment of heart failure over the last quarter century has been directed toward inhibition of the initially adaptive and ultimately maladaptive neurohormonal response to low cardiac output. The most studied and effectively inhibited neurohormonal system has been the renin-angiotensin-aldosterone system. ACE inhibitors have been studied in many large prospective randomized trials in adults with heart failure, in which more than 7000 adults have been enrolled. These studies conclusively demonstrated that these agents improve symptoms and survival in adults with HFrEF and delay the onset of symptoms in asymptomatic patients. They work through the inhibition of ACE, which inhibits the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. ACE identical to kininase II, thus having an additional action of increasing bradykinin levels. This is thought to be responsible for the relatively frequent side effect of cough seen in some patients who take these agents. They also reduce afterload, preload, and systolic wall stress. ACE inhibitors are currently recommended for all adult patients with stage 3 heart failure (those with current or previously symptomatic HFrEF unless the patient is intolerant of them.
The data on the efficacy of ACE inhibitors in children with heart failure are less robust. Many small studies from the 1980s and 1990s suggested that they may be beneficial in children with heart failure due to left-to-right shunts. A few small retrospective reports also suggested a possible benefit in children with decreased systolic ventricular function. One prospective randomized trial compared the effects of enalapril with placebo in children who had undergone the Fontan operation. The primary end point was exercise capacity, and no difference was found between the two groups after 10 weeks of therapy. In fact, the mean percent change from rest to maximal exercise was significantly decreased in the enalapril group compared with those on placebo. Another study compared two groups of postoperative patients at two different hospitals, one receiving ACE inhibitors and one not. Those receiving the ACE inhibitors had a decreased duration and amount of pleural drainage.
ARBs have been shown to be beneficial in the treatment of heart failure in adults but not superior to ACE inhibitors. Thus, ARBs are currently recommended for the treatment of HFrEF in adults, primarily those who are intolerant of ACE inhibitors. There is very little experience with ARBs in children. Studies of ACE inhibitors and ARBs in young adults with congenital heart disease and heart failure due to dysfunction of a systemic right ventricle have failed to show a clear clinical benefit.
β-Blockers
Waagstein and colleagues first reported the beneficial effects of β-blockade in a small group of adults with heart failure in 1975. Many small studies over the next 20 years suggested some benefit from metoprolol, bisoprolol, and carvedilol in adults with stable, chronic HFrEF. However, it was not until 1996 that two large prospective randomized trials of carvedilol conclusively demonstrated that β-blockers improve symptoms, survival, and ventricular remodeling in adults with mild to moderate HFrEF ( Fig. 65.5 ).
