i. Management of Heart Failure in Children Duraisamy Balaguru, MBBS, DCH, MRCP(UK), Michael Artman, MD, and Marcelo Auslender, MD B dvances in our understanding of the pathophys- iology and molecular basis of diseases offer new, challenging, controversial, and some- times, counterintuitive forms of therapy. This is espe- cially true with regard to the syndrome of heart failure. Therapeutic approaches to heart failure in adults have evolved rapidly during the past decade. Unfortunately, as with many other aspects of medicine, our concepts of heart failure in the pediatric population have been reduced to a simple extrapolation of the adult model. Pediatricians know that a child is not a small adult. Consequently, heart failure is perhaps a far more com- plex entity in the pediatric population with regard to pathophysiology and the possible courses of action. In this review we summarize recent advances in heart fail- ure research in adults and attempt to integrate these findings in a pediatric context. The basic paradigm of hemodynamic derangement and the consequent symptoms have dominated our approach to congestive heart failure for most of this century (Fig 1). Despite constraint by this narrow view- point, the normalization of hemodynamics has an immediate positive effect on symptomatic improve- ment. Multiple clinical trials were conducted in the adult population with a variety of pharmacologic strate- gies aimed at enhancing systolic performance only. The clinical outcome of these trials was disappointing because of adverse effects on the heart in the long term, since the initial improvement in the standard measures of heart failure severity (such as exercise tolerance, symptoms, and hemodynamics) was not sustained. 1,2 Application of information available from recent heart failure research enables us to go beyond the concept of the heart as a simple pump and formulate a more com- prehensive understanding of the syndrome of heart fail- ure (Fig 2). We are now beginning to recognize the pos- From the Department of Pediatric Cardiology, New York University Medical Center, New York, New York. Curr Probl Pediatr 2000;30:5-30. Copyright © 2000 by Mosby, Inc. 0045-9380/2000/$12.00 + .15 83/1/97151 itive and negative consequences of treatment aimed at simply improving cardiac pump performance. We now know that the development and progression of heart fail- ure result from a complex interplay of hemodynamic and neurohormonal factors. Heart failure is now viewed as a clinical syndrome that incorporates hemodynamics and compensatory neurohumoral responses in the over- all paradigm. New developments in our understanding of heart failure as a pathophysiologic syndrome are derived from the following advances. 1. Today the principal components of the major sig- naling pathways involved in cardiac and vascular cell function and regulation are better defined. 3-5 15urthermore, the importance of cross-communi- cation and interplay among the various regulatory pathways is increasingly apparent. 2. The essential role of Ca 2+ in cellular homeostasis is maintained by complex interactions among many signaling systems. 3. It has long been known that during the decompen- sated phase of heart failure the sympathetic ner- vous system (SNS) and the renin-angiotensin sys- tem (RAS) are activated. New insights into the molecular signaling pathways involved have pro- vided a better understanding of the role of these compensatory mechanisms in cardiac and vascu- lar remodeling. 4. New discoveries relative to the role of autocrine and paracrine factors, including angiotensin, endothelin, peptide growth factors, nitric oxide (NO), and prostacyclin, provide insights into the development of both cellular adaptive and mal- adaptive mechanisms in heart failure. 5. More rational pharmacologic strategies are emerging that are directed more precisely at the cellular and molecular abnormalities associated with the heart failure syndrome. This presentation primarily focuses on the manage- ment of the patient in a compensated state of heart failure. The multifactorial causes responsible for Curr Probl Pediatr, January 2000 5
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`rl.emodynami s I I ~eart Failure 1 I I Symptomsl FIG I. Traditional heart failure pathophysiology paradigm used in the past decades. The 2 basic paradigms, hemodynamic derangement and the consequent symptoms, have dominated our approach to con- gestive heart failure for most of this century. In the previous few decades, multiple clinical trials were conducted in the adult population with vasodilators, positive inotropes, and inodilators as strategies to enhance systolic performance. These studies mostly demonstrated worsening of the natural history of heart failure in the long term, in spite of hemodynamic improvement in the short term. CO, Cardiac output. l omoayn 1 L eurohormo a, I u tYl ~ ~-~ ~usclo isufo~.~ I I I I t FIG 2. Current heart failure pathophysiology paradigm used. Current pathophysiologic paradigm that unifies the understanding of mecha- nisms that are active in the syndrome of heart failure. ANP, Atrial natriuretic peptide; CO, cardiac output; HF, heart failure; RAS, renin- angiotensin system; SNS, sympathetic nervous system. development and progression of the heart failure syn- drome are presented as a link to understanding contro- versial therapies such as the use of digoxin and ~3- blockers. A short section is dedicated to the care of the neonate with a congenital heart defect because this is a relatively common problem confronting pediatri- cians. This review departs from more traditional pre- sentations of pediatric heart failure in that the simple enumeration of signs and symptoms for each particu- lar disease state has been avoided. Rather, we attempt to present a more physiologically based approach that allows a grouping of different anatomic defects into similar clinical scenarios. Definitions There is no single definition that encompasses the syndrome of heart failure in all of its facets. As a con- sequence, there are several definitions, depending on how heart failure is viewed. The following is a classic definition of the disease state, congestive heart failure: "Cardiac failure is the inability of the heart to deliver oxygen to the tissues at a rate commensurate with the metabolic demands. ''6 The clinical entity shock is defined in similar terms: "Shock is an acute complex state of circulatory dysfunction that results in failure to deliver sufficient amounts of oxygen and nutrients to meet tissue metabolic demands. ''7 At the outset, it appears as though the same clinical state is being described with 2 different terms. So how should the definitions be modified to differentiate more clearly between heart failure and shock? The fol- lowing 2 very different clinical scenarios illustrate the difference: Case 1 relates to a child with an anomalous origin of the left coronary artery from the pulmonary artery, poor coronary collateral circulation, severely depressed myocardial function, and ongoing metabol- ic acidosis due to low cardiac output. Case 2 involves a different child, with a cyanotic heart defect with diminished pulmonary perfusion, severe hypoxemia, normal myocardial function, and ongoing metabolic acidosis due to anaerobic metabolism. Both cases fit either of the definitions mentioned above. However, although any improvement in cardiac function may arguably favor the patient in the first case, similar maneuvers will have little if any benefi- cial effect in the second patient. These examples illus- trate the limitations inherent in adhering to the restrict- ed definition of heart failure on the basis of only oxy- gen delivery and metabolic demand of the target tis- sue, rather than the heart and its regulatory mecha- nisms. If we were to consider heart failure as simply an acute pump failure resulting in inadequate oxygen delivery, then the rationale for attempts to restore con- tractility toward normality would be sound in the short term. With this strategy in mind, manipulation of myocardial loading conditions and systolic function with pharmacologic agents formed the traditional basis for patient management and improved systemic oxygen delivery. Although this may be appropriate in the case of acute, decompensated low cardiac output state (which may be considered to be synonymous with "cardiogenic shock"), this approach is not satis- factory for chronic, compensated heart failure states. 6 Curr Probl Pediatr, January 2000
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`Sustained inotropic stimulation of the failing heart can produce deleterious effects in the long term. At least 4 potential problems may be encountered during sus- tained positive inotropic therapy: (1) an increase in the rate of myocardial energy expenditure, resulting in a mismatch between oxygen availability and oxygen demands; (2) abnormalities in the processes governing contraction and relaxation; (3) an increase in intracel- lular calcium concentration, which may promote trig- gered arrhythmias; and (4) an uncoupling of the respi- ratory chain leading to further energy starvation. 8,9 A better definition of heart failure is necessary to encompass all of the compensatory mechanisms of heart dysfunction. Furthermore, should we define heart failure differently in the pediatric population? The spectrum of pediatric cardiac disease does go beyond the simple anatomic abnormality in need of surgical intervention. However, irrespective of the underlying primary etiology, the heart failure syndrome has cer- tain common characteristics. Milton Packer 1° defines congestive heart failure as the following: "Heart failure is now thought as a disorder of the circulation, not merely a disease of the heart. Heart failure develops not when the heart is injured, but when compensatory hemodynamic and neurohormonal mechanisms are overwhelmed or exhausted." To this we add that heart failure develops not only when the com- pensatory mechanisms are overwhelmed and exhausted but also as a consequence of the actions of these same compensatory mechanisms. Signs and symptoms of heart failure result from interactions of a malfunction- ing pump and the physiologic responses in attempting to sustain vital functions. The development of signs and symptoms represents an acute decompensation in the setting of a long-term attempt to maintain vital function by the body's own compensatory mechanisms. This understanding of the coexistence of acuity and chronic- ity is important to us in pediatrics, where surgical palli- ation prevails over complete repair of structural defects. With these concepts in mind, we offer the following definitions as a framework for understanding and addressing the pediatric heart failure syndrome. Chronic Heart Failure Syndrome (Compensated State) Chronic heart failure syndrome is a cardiac pump dysfunction with activation of compensatory respons- es that ultimately contribute to silent and progressive deterioration of myocardial function. Patients with this syndrome may exhibit few, if any, symptoms of "congestive" heart failure because systemic compen- satory mechanisms, mainly activation of the SNS and the RAS, maintain homeostasis. However, sustained SNS and RAS activation promotes progression of dis- ease mediated by paracrine and autocrine factors./1 These points are further expanded in the section about the pathophysiology of heart failure. Acute Heart Failure Syndrome (Decompensated State) Acute heart failure syndrome is an acute functional uncoupling between compensatory mechanisms and depressed myocardial pump function leading to homeostatic imbalance and overt symptoms. The development of symptoms or the worsening of a pre- vious clinical state marks the beginning of decompen- sation and acute heart failure. Additional myocardial injury, increased metabolic demands, or changes in loading conditions may bring about this new clinical state. Symptoms of fluid retention develop or progress primarily as a consequence of peripheral vasoconstric- tion and sodium retention. Congestion, a word closely identified with heart failure, is only 1 manifestation and is a minimal part of the overall heart failure syn- drome. According to our conceptual framework for pediatric heart failure syndrome, a congested circula- tory state represents a decompensated state. Shock Shock is a state of acute circulatory dysfunction with completely overwhelmed physiologic compen- satory mechanisms. Shock can result from a variety of causes with cardiogenic shock occurring infre- quently in the pediatric population. Because the nor- mal physiologic responses are completely inadequate to maintain circulatory homeostasis, shock must be corrected promptly to prevent death. The pathophysi- ology and treatment of shock are beyond the scope of this review and are not fully discussed. Etiology of Heart Failure in Children Numerous primary causes of the heart failure syn- drome exist in the pediatric population. In many cases, precise determination of the underlying cause is cru- cial for defining optimal therapy, especially for anatomic, metabolic, toxic, and infectious etiologies. Table 1 provides an etiologic classification of heart Curr Probl Pediatr, January 2000 7
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`TABLE t. Etiologic classification of heart failure in children Anatomic (congenital and acquired) Arrhythmias Infections Metabolic errors Tumors Drugs Toxins L-R shunts Valvar obstruction Valvar regurgitation Hypertension Cardiomyopathy Loss of myocardium Viruses, HIV, mycobacteria, bacteria, fungus, and parasites Inborn errors of metabolism, storage disorders, hyperthyroidism, adrenal insufficiency, carnitine deficiency I~Blockers, calcium channel blockers, antiarrhythmics, chemotherapeutic agents, antiviral agents Ethanol, cocaine, hypoxia, metals CHF, Chronic heart failure, failure in children. Anatomic congenital heart defects display an age dependency in the development of signs and symptoms of congestive heart failure. Pulmonary vascular resistance is the single most important factor determining the degree of severity and time of onset of heart failure in patients with excessive pulmonary blood flow (left-to-right [L-R] shunt lesions) or duct-depen- dent lesions. The severity of flow obstruction, either arterial (aortic and pulmonary stenosis, coarctation of the aorta) or venous (total anomalous pulmonary venous connection [TAPVC]), is also an important determinant not only of time of presentation but also of the clinical picture. Although shock is a common pre- sentation of obstructive lesions in the neonatal period, heart failure predominates in infants (see later in "Clinical Manifestations" section). Patients with coarc- ration of the aorta have systemic hypertension in infan- cy and childhood. While correction of the anatomic defect may normalize blood pressure, the substrate exists for the development of hypertension later on in life, although the mechanism of hypertension is still unclear in such patients. Patients with anomalous origin of the left coronary artery from the pulmonary artery display a bimodal clinical picture. Patients with poorly developed collateral coronary circulation are seen early in life with signs and symptoms of cardiogenic shock resulting from myocardial infarction (muscle loss, mitral regurgitation). Patients with adequate collateral circulation are seen later on in life with signs of heart failure and dilated cardiomyopathy. Acquired factors are the result of therapeutic inter- ventions designed to treat anatomic defects that lead to congestive heart failure. Persistent arrhythmias can worsen heart function in patients who have undergone multiple surgical interventions. This is an unfortunate, long-term complication of procedures such as the atrial switch operation (Mustard or Senning procedures) for transposition of the great arteries, tetralogy of Fallot repair, and the Fontan procedure for single ventricle defects (single ventricle bypass surgery in which the systemic vena cavae are directly connected to the pul- monary arteries). ~2 Right ventricular dilatation with poor systolic and diastolic function is a recognized late complication after repeated operations for the recon- struction of the right ventricular outflow tract. 13,14 Ventricular injury is linked to valvar obstruction-regur- gitation physiology and the consequent development of myocardial hypertrophy and fibrosis. The need for sev- ern operative procedures exposes the myocardium to repeated ischemic and reperfusion injury. Inborn errors of metabolism such as Pompe's disease or carnitine deficiency may display a certain relationship to time in terms of age of onset of symptoms. However, there are other etiologic factors that show a more or less similar incidence across the pediatric age span, such as infec- tion, inflammation, tumors, and toxins. Pathophysiology of Heart Failure The pathophysiology of heart failure is now a multi- thceted entity that encompasses several systems that were not previously thought significant with respect to heart failure (Fig 2). The compensatory mechanisms that control cardiac function have been studied and are targeted in the treatment of heart failure syndrome, especially in the chronic compensated states. Furthermore, developmental changes in the heart and its control mechanisms at different levels have to be taken into account while treating a child in heart fail- ure with medications that were tested mostly in adults. Developmental Stage and Age of the Patient The pediatric age is perhaps unique in its intimate relationship to surgical intervention. Today, surgery is timed not only according to the presence of anatomic disease and failure of medical therapy, but also according to consideration of myocardial cell adapta- tion and chamber remodeling. The latter is well illus- trated in the timely fashion with which the multiple surgical steps to the single ventricle heart are planned. In pediatric heart failure, surgery can end decompen- sation (acute heart failure), which is clearly demon- strated in patients with large L-R shunts (eg, patent 8 Curr Probl Pediatr, January 2000
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`ductus arteriosus [PDA], ventricular septal defect [VSD]). Surgical intervention can also slow the pro- gression of the compensated state (chronic heart fail- ure) through palliative procedures. The child's age is an important factor not only in the planning of surgery but also in the mode of presenta- tion of the disease. As much as it is true that a child is not a small adult, a neonate is not a small child. Significant differences exist in the neonatal myocardi- um, which together with ongoing maturation process- es in other organs, make the pharmacologic approach to the newborn child unique (see the "Immature Heart" section). The relaxation of the pulmonary vas- culature determines the time of symptomatic manifes- tation of a disease existent at birth (eg, VSD, PDA, and atrioventricular [AV] septal defect). The issues related to age and onset of symptoms are further addressed later in the section on clinical presentations. Organ Dysfunction The hemodynamic abnormalities in patients with heart failure are relatively simple. Systemic cardiac output may be insufficient because of either reduced ejection of blood into the great arteries (systolic dys- function) or inadequacy of the heart to receive venous return (diastolic dysfunction). In heart failure, the interaction between the contractile (inotropic) and relaxation (lusitropic) properties of the heart is altered. At end diastole, intraventricular pressure and volume are determined by preload (venous return) and the lusitropic state of the ventricular myocardium. On the other hand, peripheral impedance, afterload, and the inotropic state of the ventricular myocardium deter- mine end-systolic ventricular pressure and volume. Systolic Dysfunction. The fundamental problem in systolic dysfunction is impaired ventricular contractil- ity. The ability to increase stroke volume with an increase in preload is therefore diminished when sys- tolic performance is impaired. 15 The normal ventricle, assuming preload (venous return) is adequate, is rela- tively insensitive to small changes in afterload. In con- trast, in a ventricle with systolic dysfunction, a very small increase in afterload may lead to a marked decline in cardiac output. Conversely, a small decrease in afterload may significantly improve left ventricular function. Afterload encompasses a variety of factors relating to the vasculature and its coupling with the ventricle. Systemic vascular resistance (SVR) and arterial pressure are important components of after- load, but large-artery impedance and left ventricular l i Compensatory Mechanisms I Increase in heart rate Increase in contractility Increase in preload Increase in contractile elements I Direct cardiotoxicity 1 Increase in SVR Increased MVO2 Increase in wall stress t I Progressive myocyte dysfunction Cell loss I 4 ]1 Progressive Decompensation II FIG 3. Path to decompensation. During the decompensated phase of heart failure, the SNS and the RAS are activated as compensatory mechanisms. Yet, a relentless progression of cardiac and vascular remodeling can be observed. Continued activation of compensatory mechanisms plays an important role in the development of the ini- tially adaptive and eventually maladaptive mechanisms that lead to decompensation. MV02, Myocardial oxygen consumption; RAS, renin-angiotensin system; SNS, sympathetic nervous system; SVR, sys- temic vascular resistance. volume may also contribute significantly. The Laplace relationship implies that the end-systolic wall stress (afterload) is proportional to both end-systolic pres- sure and end-systolic volume. When ventricular sys- tolic function is reduced, end-systolic volume increas- es, which when coupled with an increase in preload, leads to an increase in afterload. 16 Diastolic Dysfunction. Diastolic cardiac dysfunction is characterized by decreased ventricular compliance, necessitating an elevated venous pressure to sustain adequate ventricular filling. Abnormal diastolic func- tion may cause symptoms of inadequate cardiac output despite normal systolic function. 15,17 The causes of diastolic dysfunction in children are listed in Table 2. Neurohormonal Factors The Path to Decompensation. Compromise in car- diac output and perfusion pressure activates acute stress mechanisms (Fig 3). The maintenance of blood flow and pressure to vital organs becomes a priority. To this end, the activity of the SNS and RAS is enhanced. This compensatory increase in neurohu- moral activity initially results in an increase in myocardial contractility, selective peripheral vasocon- Curr Probl PedJatr, January 2000 9
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`TABLE 2. Causes of primary diastolic dysfunction in children Obstruction to ventricular filling AV valve stenosis Pulmonary venous obstruction Cor triatriatum Anomalous pulmonary venous drainage with obstruction Systemic venous obstruction after atrial switch operation Poor hemodynamics after the Fontan procedure Single ventricle dysfunction AV valve regurgitation High pulmonary vascular resistance Pulmonary parenchymal disease Systemic venous obstruction Pericardial or external constraints Reduced ventricular compliance Left ventricular hypertrophy Systemic or pulmonary hypertension Cardiomyopathies Transplant rejection striction, fluid and salt retention, and maintenance of blood pressure. A new state of homeostasis occurs at a higher baseline of SNS and RAS activity. However, when the low cardiac output becomes chronic, the same responses that were beneficial in maintaining circulatory homeostasis in acute heart failure actually accelerate myocardial cell death and exacerbate the hemodynamic abnormalities. The excessive activation of vasoconstrictor systems goes together with a loss of counterregulatory vasodilator influences (NO, prosta- cyclin). 11,18,19 Loss of these compensatory mecha- nisms adds to the burden of the failing heart. Although activation of the SNS and RAS is effective in short-term compensation, the adverse consequences of continued activation of these systems eventually overcome the initial benefits. The following are some of the well-known adverse consequences. 1, Myocardial oxygen consumption increases because of a rise in the heart rate, contractility, and wall stress, which may exceed oxygen deliv- ery to the myocardium. 2. Increased interstitial collagen may account for reduced capillary density and increased oxygen diffusion distance. 3. Activation of the hypertrophic response increases the number of functioning contractile elements. In addition, alterations in gene expression involving calcium homeostasis and changes in contractile proteins or their regulatory mechanisms occur that may produce an inefficient contractile apparatus. 4. Direct cardiac toxicity occurs because of increased activity of the SNS and RAS due to a loss of cardiac myocytes that occurs through 2 general mechanisms, necrosis and apoprosis. 2°,21 The first mechanism is necrosis, which occurs through a variety of cytotoxic mechanisms and may be observed in situations of both acute and chronic myocardial dysfunction. It is a passive process charac- terized by cellular swelling and inflammation. The second mechanism is apoptosis, which is an active process that involves activation (or lack of suppres- sion) of genes encoding for programmed cell death. Although the data are limited in adults' hearts, the intermediary factors responsible for apoptosis appear to be upregulated by angiotensin II receptors, among others.22 Apoptosis appears to be activated in the con- text of vascular remodeling, hypertension, ischemia- reperfusion states, and other circumstances that pro- mote ventricular remodeling. Cellular Factors The failing heart, as alluded to above, is likely to be in a state of "energy starvation. ''23 In severe, long-stand- ing heart failure, myocardial cells begin to die. Myocyte necrosis stimulates fibroblast proliferation, so that the myocardial cells are replaced with connective tissue collagen. 24 As the loss of cardiac myocytes progresses, the failing heart begins to dilate. According to Laplace's law, the dilatation increases wall tension (afterload) and establishes a vicious cycle that further overloads the cells of the failing heart. A decrease in capillary densi- ty and a relative deficit of mitochondria contribute to the energy starvation. 25 Relaxation is more sensitive than contraction to energy deficit. Calcium entry into the cytosol to initiate systole consumes less energy than the extrusion of calcium from cytosol to cause relax- ation. 26 In this manner, systolic dysfunction may subse- quently promote diastolic dysfunction. Abnormal Gene Expression Hypertrophy initially helps compensate for an acute overload by decreasing wall tension and afterload. However, long-standing hypertrophy is accompanied by abnormalities in gene expression that are detri- mental to efficient functioning of the overloaded heart. Changes in actin, myosin, and collagen iso- forms have been described in different models of heart failure and remodeling. 27,28 Cardiac remodeling in its early stages leads to salu- tary effects, such as a reduction of wall tension, an increase in myocardial efficiency, and energy sparing. 10 Curr Probl Pediatr, January 2000
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`~-- Ca 2+ Ca2+ ~I~ Ca 2+ [/ Ca =+ P~Ca 2+ Ca2+ M A Na + FIG 4. Mechanisms of calcium flux in adult cardiac myocytes. This figure represents the factors governing the contraction and relaxation in adult cardiac myocytes. For clarity, events related to calcium fluxes occurring during systole are represented on the left side of the figure and those of diastole on the right side. Thicker arrows indicate a relatively higher role for the specified pathway in calcium flux. Adult cardiac myocytes have a well-developed SR, which plays a prominent role (represented by thicker arrows) in the increase and decrease of cytosolic calcium con- centration. There are well-developed T tubules in the sarcolemma bringing L-type calcium channels in proximity to the calcium release channels of the SR. A & M, Actin and myosin myofilaments; Mito, mitochondria; NCX, Na+-Ca 2+ exchanger; RyR, ryanodine receptors. However, in the long term, remodeling leads to myocar- dial cell death, fibrosis, reduction in capillary density, mitochondrial deficiency, and chamber dilation. Remodeling of the heart and of the ventricles in par- ticular occurs in response to changes in loading con- ditions. Remodeling alters the cardiac structure and, in turn, its function and coronary blood flow. 29 The myocyte compartment of the heart muscle responds by hypertrophy. Changes in loading conditions cause a stretched-induced release of paracrine and autocrine angiotensin II that, through intracellular signal path- ways, leads to changes in transcription and gene expression resulting in myocyte hypertrophy. Independent of the hemodynamic status, the nonmyo- cyte compartment or the mesenchymal tissue of the heart also responds to angiotensin II and aldosterone autocrine and paracrine stimuli. Aldosterone acts specifically on fibroblasts and promotes collagen syn- thesis. Increased production of collagen alters the proportion of the myocyte-to-nonmyocyte compart- ment of the ventricular myocardium. This leads to increased stiffness of the ventricular wall and causes diastolic dysfunction. 24 Evidence suggests that spironolactone decreases ventricular fibrosis. 3° It is also known that aldosterone may "escape" inhibition by angiotensin-converting enzyme inhibitor (ACEi) therapy. Addition of the aldosterone-receptor antago- nist (spironolactone) is being studied. Data from the RALES pilot study (the Randomized Aldactone Evaluation Study) in adults indicate that beneficial effects are obtained by the addition of spironolactone to the conventional heart failure therapy, including an ACEi. 31 In addition, stretch-sensitive calcium chan- nels have been implicated in cardiac remodeling. As a result of membrane deformation, intracellular calci- um level increases and initiates growth. 32 Increases in loading conditions have also been associated with reexpression of fetal genes, early response genes (c- los, c-jun, c-myc), and atrial natriuretic peptide (ANP), all early markers of cardiac hypertrophy. Abnormal Autonomic Responses Compensatory sympathetic stimulation initially elic- its important chronotropic, inotropic, and lusitropic responses that improve circulatory function in patients with acute heart failure. Myocytes in the failing heart ultimately lose their ability to respond normally to [3- adrenergic receptor ([3AR) agonists. A decreased num- ber of functioning ~AR molecules (downregulation) occur during sustained sympathetic overstimulation. Curr Probl Pediatr, January 2000 11
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`Ca2+ Ca 2+ Ca 2+ ~ Ca2+ I J Ca 2+ Ca2, "" Na + FIG 5. Mechanism of calcium flux in neonatal cardiac myocytes. This figure represents the mechanisms occurring in an immature cardiac myocyte. The processes are represented using the similar principles and abbreviations as described in Fig 4. Note the poorly developed SR, relatively scarce contractile proteins, and absence of T tubules. The thick arrow from NCX represents a larger role for it in calcium flux in an immature myocardium. The contribution from the SR is smaller. Several recent reports indicate that the levels of G s, a stimulatory G protein that couples the BAR with adenylyl cyclase, are decreased in heart failure. Conversely, G i, an inhibitory G protein that inhibits cyclic adenosine monophosphate (cAMP) production is increased in the failing heart. The resulting decrease in Gs/G i substantially alters the responsive- ness to AR stimulation. 33-36 The Immature Heart In most mammals, important changes occur during cardiac myocyte development and maturation, which continue after birth. Newborn myocytes are different from the adult cells in their mechanisms of calcium regulation and in their responses to physiologic and pharmacologic interventions. In addition, developmen- tal changes in the autonomic nervous system and ARs occur that lead to differences in response between new- born and adult myocytes to