EMERGING THERAPIES FOR CHRONIC HEART FAILURE IN CHILDREN AND YOUNG ADULTS
Bibhuti B Das, Robert SolingerDivision of Cardiology, Department of Pediatrics, University of Louisville , Louisville , KY 40202b
Address for correspondence : Bibhuti B Das, MD, Division of Pediatric Cardiology, Suite # 334, University of Louisville, Louisville, KY 40202, USA.E-mail: firstname.lastname@example.org
The pace at which the base of knowledge has expanded, and the number of new studies published, there is a need to rethink future management of heart failure in children and young adults. The clinical evidences from adults suggest that the neurohormonal explanation of progression of heart failure is not complete and ventricular remodeling is an important pathophysiologic mechanism for initiation and progression of heart failure. Therefore, treatment of heart failure should be aimed both at neurohormonal modulation and at reversing the ventricular remodeling process. In this review we have discussed not only conventional remedies, but also newer drugs and therapies that are on the horizon, including angiotensin-converting enzyme inhibitors, beta-blockers, exogenous brain natriuretic peptide (nesiritide), blockers of angiotensin-receptors, calcium sensitizing agents, modulation of the cytokine response, endothelin receptor antagonists, vasopressin antagonists, chronic resynchronization therapy and/or implantable defibrillator, and implantable circulatory assist device support for heart failure in children and young adults. The need to care effectively for the increasing population of children and young adults with heart failure urges more prospective controlled studies in children to improve prognosis of heart failure. Key Words : pediatric heart failure, left ventricular remodeling, carvedilol, nesiritide, levosimendan, cardiac resynchronization therapy, ventricular assist device, pediatric heart transplantation
As per the American College of Cardiology/American Heart Association task force on practice guidelines published in 2005 the term "heart failure" is preferred over the older term "congestive heart failure". (1) Even after two decades of success with neurohormonal inhibition, heart failure still remains the number one killer in adults and many patients still experience progression of their disease. (2) In children, the scope of the problem is less well defined. Data from the Pediatric Cardiomyopathy Registry published in 2004 indicated an annual incidence of 1.13 cases of cardiomyopathy per 100,000 children. (3) While some of this represent asymptomatic disease, nonetheless, the burden of disease overall is quite high. In the Pediatric Cardiomyopathy Registry, the majority of children with cardiomyopathy also had heart failure , with mortality rate of 13.6% at 2 years in dilated forms of cardiomyopathy. (3) It has been estimated that the annual incidence of heart failure from structural defects is 0.1-0.2% of live births. (4) The American College of Cardiology/American Heart Association -2005 guidelines excluded heart failure in children for two reasons: (1) because the underlying causes of heart failure in children differ from those in adults and (2) because none of the controlled trials of treatments for heart failure have included children. (1) Although the etiology of heart failure in adults is different from children, hemodynamic consequences and neurohormonal activation are remarkably similar. (5-8) In 2004, the practice guidelines for management of heart failure in children was published and followed the format of adults heart failure guidelines. (9) This review discusses what is known and not known about the relative efficacy and safety of available treatment choices for our growing populations of children and young adults with heart failure.
Despite advancement in surgical management, chronic heart failure in children is frequently associated with congenital heart disease. Chronic heart failure occurs most commonly in these patients as a result of excessive ventricular volume overload, pressure overload, post-operative cardiac sequelae with residual lesions or myocardial damage, pulmonary vascular disease, or consequence of chronic hypoxia. Other causes of chronic heart failure in children are cardiomyopathy (hypertrophic, dilated, restrictive, or non-compaction), congenital or acquired coronary artery abnormalities, endocarditis, Eisenmenger syndrome, primary pulmonary hypertension, cor pulmonale, incessant tachyarrhythmias, chronic anemias, and rheumatic heart diseases. Among the cardiomyopathy, dilated cardiomyopathy accounts for most cases of chronic heart failure in children. The underlying cause of dilated cardiomyopathy includes a wide variety of etiologies: idiopathic, inherited, infective, infiltrative, nutritional, iatrogenic or toxic, and cardiomyopathy associated with generalized muscle disease or mitochondrial disorders. Generally 30% of cases of myocarditis result in chronic heart failure . (10) Mason et al found evidence of myocarditis in 10% of adults with new-onset heart failure who did not have coronary heart disease. It is likely that this figure is much higher in children without structural heart disease. (11)
Heart failure may be defined as that pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the metabolic requirements of the body. (12) The heart may fail if it is confronted with: (1) a n excessive preload, i.e. increase in tension in ventricular cardiac muscle fibers leading to excessive expansion of ventricles in diastole as seen in left to right shunt, mitral regurgitation and complete heart block; (2) abnormally high afterload as in hypertension, coarctation of the aorta and aortic stenosis; (3) impaired myocardial contractility as in myopathy, myocarditis; and (4) inadequate diastolic filling as in hypertrophic or restrictive cardiomyopathy, constrictive pericarditis and tachyarrhythmias. Chronic heart failure is a clinical syndrome in which heart disease reduces cardiac output, increases venous pressures, and is accompanied by molecular abnormalities that cause progressive deterioration of the failing heart and premature death of myocardial cells. (13) At the onset of heart failure various compensatory mechanisms with salutary effects come into play. But the same compensatory mechanisms if pressed into play indefinitely potentiate heart failure , the possible mechanisms of which are described below.
The compensatory increase in sympathetic tone increases the heart rate, augments myocardial contractility and causes systemic vasoconstriction which help to maintain tissue perfusion pressure. But when sympathetic action is undeterred, tachycardia and peripheral vasoconstriction (increased afterload) leads to substantial increase in cardiac work and myocardial oxygen consumption. Furthermore, at the cellular level, compensatory gain in cardiac excitation-contraction coupling mediated by sympathetic stimulation ultimately become unsuccessful as evidenced by unwanted diastolic leak of sarcoplasmic reticulum calcium leading to depletion of intracellular calcium and loss of contractility. (14-15 )
The compensatory stimulation of renin-angiotensin-aldosterone system causes vasoconstriction and renal retention of salt and water which increases diastolic filling pressure and increase myocardial contractility through Frank-Starling mechanism. (16) But when these effects are excessive, it causes systemic and pulmonary venous congestion and increases after load. In addition, renin-angiotensin-aldosterone system is responsible in mediating renal hyporesponsiveness to the natriuretic peptides, which facilitates progression of heart failure . (17) The compensatory ventricular hypertrophy initiated and regulated by many of the signaling molecules that mediate the neurohormonal responses in the failing heart provides more contractile elements. However, maladaptive hypertrophy ultimately results in myocardial cell death and fibrosis.
An inflammatory response secondary to increased wall stress and stretching of myocardial fibers results in production of cytokines and free radicals leading to apoptosis. If uninterrupted, apoptosis will lead to necrosis, fibrosis and further dysfunction. (13-14) The extracellular matrix remodeling is promoted by neurohormonal activation and activation of pro-inflammatory cytokines. Increase plasma levels of matrix metalloproteinases are associated with severe heart failure and probably reflect progressive remodeling. (18) There is up-regulation of myocardial matrix metalloproteinases associated with decreased fibrillar collagen cross-link formation in patients with chronic systolic heart failure with cardiomyopathic ventricles.
Heart failure is a clinical syndrome consisting of signs and symptoms that arise from congested organs and hypo-perfused tissues. Impaired myocardial function results in cardiomegaly, tachycardia, gallop rhythm, poor peripheral perfusion and growth retardation. Cardiomegaly occurs in most patients with heart failure except in pulmonary venous obstruction and constrictive pericarditis. A sleeping heart rate above 160 per minute in infants and above 100 per minute in children is usually present in heart failure . A protodiastolic gallop at the time of rapid ventricular filling is a sign of impaired ventricular function. Poor peripheral perfusion manifests itself by cold extremities, weak pulses and low blood pressure associated with skin mottling. Growth retardation is noted in infants with chronic heart failure . Dyspnea and tachypnea are the typical signs of increased pulmonary venous pressure. Respiratory rates may be as high as 80-100 per minute and are associated with retraction, grunting and poor feeding. Wheezing may be the earliest and occasionally the only evidence of pulmonary edema. Rales are relatively uncommon sign of pulmonary edema in the pediatric age group. Cyanosis , in the absence of intracardiac right to left shunt, may be present and is secondary to impaired pulmonary gas exchange as well as due to sluggish peripheral circulation. Signs of systemic venous congestion include hepatomegaly and peripheral edema. Exercise intolerance is an important feature of heart failure in older children and young adults.
It is to be remembered that heart failure is a clinical syndrome and for the most part is not associated with a diagnostic laboratory test. The chest radiograph shows cardiomegaly and increased pulmonary vascular markings. Electrocardiograph is not helpful in the diagnosis of heart failure except when secondary to tachyarrhythmias, heart block or myocardial ischaemia. Serum brain type natriuretic peptide is a relatively new biochemical marker which has proven to be very useful in the diagnosis of heart failure , especially in patients with acute dyspnea In such a setting, brain type natriuretic peptide levels more than 500 picogram per milliliter have a 90% predictive value for the presence of heart failure and levels less than 100 picogram per milliliter have a 90% predictive value for the absence of heart failure . Brain type natriuretic peptide levels between 100 and 500 picogram per milliliter are somewhat less helpful, and other tests may be needed for diagnosis . (19) Serum brain type natriuretic peptide level in heart failure patients helps to guide and monitor therapy, detects preclinical disease, and possibly reduces the need for cardiac imaging. Echocardiography is perhaps the most useful test in understanding the mechanism and cause of heart failure in children and young adults. Decreased shortening fraction and ejection fraction, and low velocity of circumferential fibre shortening are direct evidence of left ventricle systolic dysfunction. Doppler-derived indices that are useful in the evaluation of heart failure include change in left ventricular systolic pressure, stress-velocity index and strain rate imaging. Assessment of left ventricle diastolic function include spectral Doppler imaging of the mitral inflow, pulmonary venous Doppler, tissue Doppler imaging and flow propagation velocities by Color M-mode echocardiography. (20) Myocardial performance index (Tei index) is a new echocardiographic parameter in global assessment of left or right ventricular function, although the value of Tei index is age dependent. In children, the normal Tei Index values for left ventricle and right ventricle are reported to be 0.35 plus or minus 0.03 and 0.32 plus or minus 0.03 respectively. (21) Metabolic exercise testing allows determination of peak oxygen consumption, anaerobic threshold, oxygen pulse, and ventilatory equivalent for carbon dioxide, which are useful to quantitate cardiovascular functional capacity. (22) Cardiac catheterization is sometimes performed in patients with heart failure unresponsiveness to conventional treatment to confirm the diagnosis and to help guide the therapy. Endomyocardial biopsy is useful in establishing the etiology of heart failure in patients with history of systemic diseases such as collagen vascular disease, infiltrative or storage disease, giant cell myocarditis and with rapidly progressive heart failure despite conventional therapy. (23)
It is reasonable to admit that most treatment strategies used in children with chronic heart failure have been extrapolated from trials in adults. Although there is good rationale for doing this, there are significant differences between the substrate for left ventricle dysfunction between children and adults. (24) In general, pharmacotherapy for chronic compensated heart failure has three goals: the rapid relief of symptoms, slowing of the pathophysiological process involved in left ventricle remodeling and increasing patient survival. Despite the standard pharmacotherapy ( Table-1 ), some children and young adults with heart failure remain in a chronic decompensated state. These patients require intravenous inotropes and vasodilator medications. Some of these patients with end-stage heart failure become inotrope-dependent, and are candidates for newer therapies including but not limited to ventricular assist device as a bridge to transplantation or recovery. Evidence-based medicine for management of pediatric heart failure does not exist at this time. Until large, multicenter trials of children with heart failure are performed, the best course for pediatric cardiologists is to follow the adult literature, cautiously introduce accepted therapies, and follow patients closely.
Diuretics are needed to relieve the volume overload and congestive symptoms, but can activate the renin-angiotensin-aldosterone axis and sympathetic nervous system. Therefore, diuretics except spironolactone have no long-term benefits and do not prevent the disease progression in chronic heart failure. Loop diuretics are preferable to most other diuretics secondary to their effectiveness and potency. Combination therapy has been shown to be more effective than monotherapy with one class at escalating dose because sequential sites in the nephron can be blocked. New diuretics called aquaretic which are vasopressin receptor antagonists are available. (25) Two vasopressin antagonists currently being used in clinical trials are tolvaptan (vasopressin receptor-2 antagonist) and conivaptan (combined vasopressin receptor-1a and -2 antagonists). (26) The potential value of these agents is the fact that they cause elimination of water, without the loss of electrolytes, thus potentially negating the need for frequent follow-up of serum electrolytes levels.
Aldosterone antagonists (spironolactone and eplerenone) have been shown to reduce mortality in adults with heart failure. (27) Plasma aldosterone levels are elevated in heart failure, both because of increased production and reduced hepatic clearance. The mechanisms of aldosterone mediated potentiation of heart failure include increased myocardial fibrosis, increased angiotensin converting enzyme and endothelin activity, increased free radical production, and decreased adrenal nitric oxide. Low dose spironolactone is considered to be an inhibitor of renin-angiotensin-aldosterone axis, rather than diuretic.
Digoxin inhibits the sarcolemmal sodium-potassium-adenosine tri-phophatase pump which results in increased intracellular sodium and subsequent increase in intracellular calcium through inhibition of sodium-calcium exchanger. This increase in intracellular calcium results in increased contractility. Other beneficial effects of digoxin include reduction of sympathetic tone and norepinephrine levels. R ecent observations suggest that digitalis may have additional effects on cardiac cell function in both the short and long term that include intracellular effects, interactions with specific sodium-potassium-adenosine tri-phophatase isoforms in different cellular locations, effects on intracellular (including nuclear) signaling, and long-term regulation of intracellular ionic balances through circulating ouabain-like compounds. (28) Digoxin improves symptoms and decreases hospitalization, but there is no evidence that it improves survival in adults. (29-30) The effect of digoxin on symptoms and /or survival in children with heart failure is unknown.
Angiotensin converting enzyme inhibitors and angiotensin receptor blockers
Angiotensin converting enzyme inhibitors are the mainstay of treatment in all patients with systolic left ventricle dysfunction. (31) The mechanism by which angiotensin converting enzyme inhibitors benefit patients with heart failure include vasodilation, ventricular remodeling, improved renal function, and blunting the hypertrophic and apoptotic effects of angiotensin II within the myocardium. (32) Angiotensin converting enzyme inhibitors appear to exhibit a class effect and all members of this class may be equally effective. Potential side effects are hyperkalemia if used concomitantly with spironolactone, cough and angioedema due to decrease degradation of bradykinin, renal dysfunction and azotemia. The low dose angiotensin converting enzyme inhibitors are recommended in patients receiving spironolactone in order to avoid potential hyperkalemia. It is recommended to start beta blocker therapy along with angiotensin converting enzyme inhibitors if there is no contraindication. Angiotensin receptor blockers directly block the effects of angiotensin II no matter which pathway of production (angiotensin converting enzyme or chymase). In adults, angiotensin receptor blockers appear to be as effective as angiotensin converting enzyme inhibitors in improving symptoms, reducing mortality, reducing wedge pressure, and increasing cardiac output. (33) If patient is intolerant to angiotensin converting enzyme inhibitors then use angiotensin receptor blockers instead. Currently angiotensin receptor blockers available are losartan, valsartan and irbesartan. There is little data available on the use of angiotensin receptor blockers in children.
The current experience of beta-blockers in children with heart failure is limited, but a number of small trials have shown beneficial effect of carvedilol. (13, 34-40) Long- term therapy with beta blockers in adults improves systolic function and energetics and reverses the pathologic remodeling process. The improvement in energetics is by reduction in heart rate, systolic and diastolic wall stress, both of which causes decrease in myocardial oxygen demand, a shift in substrate utilization from free fatty acids to glucose, and shift in the phenotyping of failing heart to more energy-efficient isoforms. Beta blockade is also associated with a change in the molecular phenotype of the heart. These include up-regulation of the gene expression of the natriuretic peptides and beta myosin heavy chain, partially prevent down-regulation of beta-2 receptor and angiotensin-2 receptor genes, and up-regulation of endothelin-A receptor and connective tissue growth factor genes. (41) Using beta-blockers to manage heart failure is a double-edged sword. The failing heart may be extremely dependent on adrenergic support to maintain circulation, and abrupt adrenergic removal may result in circulatory collapse. Beta-blockers are usually added to angiotensin converting enzyme inhibitors and other decongestive measures if patient is clinically stable. The purpose of beta-blocker therapy is to slow the progression of the disease. Beta-blockers are not to be added as rescue drugs in patients who are decompensating. The improvement in ventricular function takes 2-3 months to develop. Before therapy is begun, patients should be informed that they may experience some worsening of symptoms for several weeks while the drug is titrated. The worsening of symptoms should be managed by adjusting the diuretics. Up-titration is performed each week and the dose is doubled until a target dosage is reached or until side effects appear. (41) Most important side effects are bradycardia and if some patients who are sensitive to bradycardia, low dose beta-blockers should be continued. If the patient on beta-blockers developed cardiogenic shock, then a phosphodiesterase type inotrope should be used rather than dobutamine as the beta receptors are saturated. Beta-blockers reported to be more useful are carvedilol, metoprolol and bisoprolol. Pediatrics studies utilized carvedilol at initial dose of 0.1 milligram per kilogram body weight per day in two divided doses and increase the dose every one to two weeks up to a target dose of 0.8 milligram per kilogram body weight per day. (34- 35, 38- 39) Pediatric experience with metoprolol and bisoprolol is very limited.
Brain type natriuretic peptide acts by the guanylate cyclase-coupled natriuretic peptide receptor-a mechanism to produce beneficial, compensatory actions, including diuresis, natriuresis, vasodilatation, and inhibition of both the sympathetic nervous system and the renin-angiotensin-aldosterone axis. In addition to its renal hemodynamic effects, natriuretic peptides have direct renal tubular actions by inhibiting angiotensin II-stimulated sodium and water transport in the proximal convoluted tubules, and inhibiting water transport in the cortical collecting ducts, through its antagonistic action for vasopressin. Furthermore, brain type natriuretic peptide reduces plasma renin and aldosterone concentrations and inhibits angiotensin II stimulated aldosterone secretion. (42) By these multiple actions brain type natriuretic peptide appears to have a significant role in protecting the heart against myocardial hypertrophy and subsequent interstitial fibrosis. Nesiritide is a recombinant human brain natriuretic peptide manufactured from E. coli with the same amino acid sequence as endogenous peptide. It is indicated for chronic decompensated heart failure. (43) The dosing is currently recommended as a two microgram per kilogram bolus followed by a continuous infusion of 0.01-0.03 microgram per kilogram per minute. The dose may be adjusted by giving a one microgram per kilogram bolus and increasing the infusion by 0.005-0.01 microgram per kilogram per minute to a maximum of 0.03 microgram per kilogram per minute. (44) Three hours time period is recommended between increasing the dose as 95% of the systemic blood pressure effect will be notable by then. The half life in patients with heart failure is approximately 18 to 20 minutes with the effect dissipating within two to four hours. Three main form of clearance are: (1) endocytosis and lysosomal degradation, (2) proteolysis by circulating neutral peptidase, and (3) renal clearance.
Neutral peptidase is an enzyme that inactivates several of the peptides like atrial natriuretic peptide, brain type natriuretic peptide, bradykinin and adrenomedullin. These peptides have vasodilator, natriuretic and antiproliferative properties. Simultaneous inhibition of neutral peptidase and angiotensin converting enzyme markedly reduces vasoconstriction, improves sodium and water balance, decrease peripheral vascular resistance and blood pressure and improves local blood flow when compared with angiotensin converting enzyme inhibition alone. The only available vasopeptidase inhibitor that has been evaluated in adults with heart failure is omapatrilat, (45) which is not yet recommended for use at this time. Candoxatril and ecadotril are oral forms of neutral peptidase inhibitors which increase levels of natriuretic peptides and are currently in trials in adult patients with heart failure. (46-47)
Endothelin receptor antagonists
Endothelin-1 levels are increased in patients with heart failure and progressively higher plasma concentrations are found in patients with heart failure as their functional class deteriorates. Endothelin-1 plasma level also correlates with pulmonary artery pressure and pulmonary vascular resistance. Although the expression of endothelin-1 within the myocardium may initially represent an adaptive response to stress, over expression of endothelin-1 may eventually be maladaptive by producing focal vasospasm, myocyte necrosis and increased myocardial fibrosis. Nonselective endothelin receptor antagonists such as bosentan, tezosentran and enrasentran are now being evaluated in clinical trials in adults but have yet to demonstrate their clinical utility. (48) Sitaxsentan is a selective endothelin-1A receptor antagonist and a selective pulmonary vasodilator, which may be useful in treating heart failure with pulmonary hypertension. (49)
Defective myocyte handling of calcium appears to be a central cause of both contractile dysfunction and arrhythmia development in heart failure. Levosimendan is a new class of calcium sensitizing drug that directly sensitizes troponin C to calcium, thus improving myocardial contractility without causing an increase in myocardial oxygen demand. (50) This sensitization is lost during diastole, allowing normal or improved diastolic function. Levosimendan also leads to vasodilatation through the opening of adenosine tri-phosphate-sensitive potassium channels. Usually this is administered as a l oading dose of 6-24 microgram per kilogram intravenously over 10 minutes followed by maintenance 0.05-0.2 microgram per kilogram per minute intravenous continuous infusion. Early experience of levosimendan in children after cardiac surgery or dilated cardiomyopathy indicates that it is well tolerated, but prospective studies are needed to evaluate the possible advantages of levosimendan over currently used vasoactive drugs. (51) Pimobendan is another calcium sensitizing agent with higher phosphodiesterase inhibitory action and also inhibits the production of inflammatory cytokines. (52)
The current interest in understanding the role tissue necrotizing factor alpha in heart failure, relates to the observation that many aspects of the syndrome of heart failure can be explained by the known biologic effects of this cytokine. When expressed at sufficiently high concentration, tumor necrosis factor alpha mimics some aspects of the so called heart failure phenotype, including (but not limited to) progressive left ventricular dysfunction, pulmonary edema, left ventricle remodeling, fetal gene expression, and cardiomyopathy. (53) Elevated levels of tumor necrosis factor alpha and other inflammatory cytokines have been associated with heart failure in children with congenital heart disease. (54) Trials with etanercept, a soluble recombinantly produced chimeric tumor necrosis factor alpha antagonist and infliximab, a monoclonal antibody against tumor necrosis factor alpha are underway for treatment of heart failure in adults. (55-56)
Coenzyme Q 10
Although coenzyme Q 10 (2, 3-dimethoxy-5-methyl-6-decaprenyl-1, 4-benzoquinone) has theoretical benefits to improve the energetics in failing myocardium by helping as an electron carrier in production of adenosine tri-phosphate, an antioxidant and free radical scavenger with membrane stabilizing properties, no beneficial effects of Coenzyme Q 10 supplementation on the left ventricular ejection fraction, peak oxygen consumption, or exercise duration are found by Khatta and co-workers. (57) Therefore, Coenzyme Q 10 is not recommended at this time until large scale clinical trials have been performed
The heart is able to utilize a variety of substrates for energy generation, including carbohydrates (glucose and lactate), lipids (free fatty acids and triglycerides), and ketones. This allows a normal heart to maintain its functional performance in a wide range of physiological conditions without experiencing an energy debt. However, an energy deficit has been observed during the development of heart failure that directly relates to patient prognosis. Long-term follow-up studies in patients with idiopathic dilated cardiomyopathy demonstrate that decreased phosphocreatinine (which is the source of instant adenosine tri-phosphate) is an independent predictor of mortality, suggesting that impaired myocardial energetics play an active role in the progression of heart failure. (58) This notion is further supported by consistent observations in clinical trials revealing that energy-costly treatment, such as positive inotropic agents (beta-receptor mimetic drugs, phosphodiesterase inhibitors) increase mortality, while energy-sparing treatments (eg, angiotensin converting enzyme inhibitors, angiotensin II blockers, or beta blockers) reduce mortality. Carbohydrates are the primary substrates for fetal hearts, while fatty acids become the predominant fuel in adult hearts, supporting more than two-thirds of the total adenosine tri-phosphate synthesized. (59) An important change in energy metabolism is observed in hypertrophied and failing heart; increasing reliance on carbohydrates while decreasing fatty acid utilization, an apparent reoccurrence of the fetal metabolic profile. (60) Studies using animal model of heart failure reveal that this shift of substrate preference is associated with the down regulation of peroxisome proliferator-activated receptor alpha, a transcriptor factor controlling the expression of key enzymes for fatty acid oxidation. (61-62) Thus, peroxisome proliferator-activated receptor alpha is an attractive candidate for the development of novel and more potent pharmacologic agents that could prove useful in reactivating the normal energy production machinery in failing hearts in the setting of cardiomyopathy.
Cardiac resynchronization therapy and/or implantable defibrillator
Conduction system abnormalities are common in patients with heart failure. Prolongation of the PR interval and QRS duration, resulting in abnormal electrical depolarization of the heart occurs in patients with heart failure secondary to systolic dysfunction. (63) The prolonged PR interval leads to a delay between atrial contraction and the onset of the ventricular contraction and may be associated with adverse hemodynamic consequences as a result of diastolic mitral regurgitation, shortened left ventricular filling time, and decreased stroke volume. (64) Ventricular dyssynchrony resulting from prolonged QRS duration enhances the hemodynamic consequences of left ventricular systolic dysfunction as a result of abnormal interventricular septal motion, with loss of septal contribution to the global ejection fraction, decreased contractility, reduction in diastolic filling times, and prolongation of the duration of mitral regurgitation. Resynchronization therapy has been studied in adults with symptomatic heart failure due to systolic dysfunction (New York Heart Association class III-IV) and prolonged QRS duration more than120 millisecond that are on standard medical therapy. (65) Biventricular pacing is one of the most promising approaches to improve or restore ventricular synchrony. A number of studies in the adult have shown that biventricular pacing is associated with acute improvements in the hemodynamics in the form of an improved maximum left ventricular pressure derivative, increased aortic pulse pressure, improved cardiac index and reduced pulmonary capillary wedge pressure. (66) Arrhythmia is a major cause of sudden death in patients with heart failure. Generally, antiarrhythmic medications have not been shown to decrease mortality in adults with heart failure, and in some instances have actually had harmful effect. (67) Many studies have shown that implantable defibrillator reduces the mortality in adults with heart failure. (68-70) Role of implantable defibrillator in children with heart failure is unknown. However, in patients who are thought to be at risk for life-threatening arrhythmias, one should consider placement of intra cardiac defibrillator in children.
Heart transplant in children of all ages is now accepted as a therapy for end-stage heart failure secondary to cardiomyopathy and palliated congenital heart disease when these diseases are life-threatening or are associated with a poor quality of life. The approach and the criterions of listing for heart transplantation in pediatric age are different than in adults. (71) Role of cardiopulmonary exercise testing is limited by lack of consensus and limited data, the adult value of peak oxygen consumption of 14 milliliter/kilogram/minute guideline does not hold true for children. (72) High pulmonary vascular resistance is another important factor affecting the perioperative mortality and outcome after transplant in pediatric age group. (73-75) The adult criteria of transpulmonary gradient (pulmonary artery mean pressure minus left atrial mean pressure) greater than 15 millimeter of mercury, may not hold true for pediatric age group, as many patients with transpulmonary gradient greater than 15 millimeter of mercury are able to undergo successful transplantation with higher transpulmonary gradient. (71) The most important limitation is availability of donor heart for our growing population of heart failure in pediatric age group and it is important to utilize this presently rare resource to benefit as many children and their families as possible.
Ventricular assist device
The clinical experience in adults have shown that prolonged left ventricular assist device can improve symptoms of heart failure by inducing neurohormonal modulation and reverse remodeling, and in some cases, lead to complete recovery. (76-78) Conventional wisdom suggests that long term ventricular assist device in children should be more useful and myocardial recovery should be better due to the plasiticity of the pediatric hearts. But, besides technical difficulties of implanting ventricular assist device in children due to their smaller size, major limiting factors are sepsis, inability to wean them from ventilator, mobilizing them and making them independent of intensive care. Therefore, the use of ventricular assist device in children compares unfavorably with the experience in adults, in whom patient extubation and mobilization often can be accomplished using numerous implantable circulatory assist devices. Since the early report of pneumatic paracorporeal ventricular assist devices in children (79) , there has been increasing use of many devices such as the Berlin Heart VAD (80) (Berlin Heart AG, Berlin, Germany), MEDOS-HIA-VAD (81) (Helmholtz Institute, Aachen, Germany), Thoratec Ventricular Assist System (82) (Thoratec Crop, Berkeley, California, USA), and Abiomed BVS-5000 (83) (ABIOMED, Inc, Danvers, Massachusetts, USA) in children. DeBakey ventricular assist device-child (Micromed Technology, Inc, Houston , Texas , USA ), the first pediatric implantable device, was first approved by United States Food and Drug Administration in 2004. Reports specifically addressing the outcomes for the longer term ventricular assist device implantation in children do not exit, and what is known must be extrapolated from scattered experiences. As the number of pediatric patients requiring ventricular assist device support increases, the science of long-term mechanical circulatory support, cellular changes in cardiac remodeling and recovery, and end-organ perfusion of pulsatile flow in pediatric patients will likely to be refined in the coming decade.
Novel approaches to treatment of heart failure
Cell replacement strategy is a new era in therapy for patients with myocardial dysfunction. It has been postulated that therapies directly targeted at replacing or regenerating damaged myocardial tissue could prevent progression to heart failure and therefore would be an important contribution to the treatment of ischemic damage to the myocardium. Many cell types have been successfully transplanted into damaged myocardium, including fetal cardiomyocytes, skeletal myoblasts, embryonic stem cells, and bone marrow-derived stem cells. (84-88) The best characterized of these is skeletal myoblast, an immature muscle cell that retains the ability to proliferate. Several studies have used human autologous skeletal myoblasts transplantation to determine if engraftment of these cells leads to long-term improvements in left ventricle function. (89-90) However, these exciting progresses have many unanswered questions including potential arrhythmic and oncogenic potential of these cells, which can only be resolved by larger clinical trials with long-term follow-up.
Table 1: Standard pharmacotherapy of chronic compensated heart failure in children
Mechanism of action
Relieve congestive symptoms; Do not change the long-term outcome
Excess use of diuretics can reduce the preload and cardiac output, resulting in neurohormonal activation and fluid retention- a vicious cycle
1 mg/kg dose BID up to max 6 mg/kg/day
10 mg/kg dose BID up to max 2 gm/day
0.1 mg/kg dose BID up to max 20 mg/day
3 to 4 mcg/kg dose BID
Increases inotropy; Attenuates neurohormonal activation; No effect on mortality
No relationship between serum digoxin level and worsening heart failure, change in left ventricle ejection fraction and exercise tolerance in adults
Angiotensin converting enzyme inhibitors
Decrease mortality and morbidity; Blocks the conversion of angiotensin I to II and activates bradykinin and kallidin; Cause vasodilation and natriuresis; Reduce afterload >
Mitigate the process of angiotensin-mediated maladaptation to heart failure; Decrease Qp:Qs and improve weight gain in children with left to right shunts
0.1 mg/kg dose TID up to max 2 mg/kg/dose
0.1 mg/kg dose BID up to max 0.5 mg/kg/day
Decrease morbidity and mortality; Carvedilol has vasodilatory, antioxidant, antiproliferative and anti apoptotic properties, Reversing cardiac remodeling
Dosing is extrapolated from adult data, extreme caution should be used because there could be exacerbation of heart failure
0.1 mg/kg dose BID up to max 1 mg/kg dose
0.05 mg/kg/dose BID up to max 0.4 mg/kg/dose
Aldosterone antagonist Spironolactone
1 mg/kg dose BID up to max 200 mg/day
Decreases mortality and morbidity; Improves endothelial vasodilator dysfunction; Suppress vascular angiotensin conversion.
Should be used with caution in patients with hyponatremia, renal insufficiency, hyperkalemia and hepatic disease
(BID=twice daily, TID= three times daily, max=maximum, Qp: Qs=pulmonary to systemic blood flow ratio, LVEDP=left ventricular end- diastolic pressure, mg/kg = milligram per kilogram)
The pace at which the knowledge base has expanded and the number of new studies published, there is a need to rethink about future management of heart failure in children and young adults caused by systemic ventricular dysfunction. We have discussed some of the current and newer drugs and therapies that are on the horizon including angiotensin converting enzyme inhibitor, beta-blocker, nesiritide, angiotensin receptor blocking agent, calcium sensitizing agent, modulation of the cytokine response, endothelin receptor antagonist, vasopressin antagonist, cardiac resynchronization therapy and/or implantable defibrillator and ventricular assist device support in pediatric patients. Most of the newer drugs are undergoing clinical trials in adults and future clinical trial designs should include pediatric population to make further progress in the management of chronic heart failure in children and young adults.
Hunt SA , Abraham WT , Chin MH , et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart failure in the Adult-Summary Article A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart failure). JACC 2005;46 :1116-43
Hunt SA, Balcer DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on practical guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol 2001; 38:2101-2113
Lipshultz SE , Sleeper LA , Towbin JA et al. The incidence of pediatric cardiomyopathy in two regions of the United States . N Engl J Med. 2003 24;348 :1647-55.
Kay JD , Colan SD , Graham TP Jr . Congestive heart failure in pediatric patients. Am Heart J. 2001; 142 :923-8.
Auslender M. Pathophysiology of pediatric heart failure. Prog Pediatr Cardiol 2000; 11: 175-84
Abraham WT, Singh B. Ischaemic and non-ischaemic heart failure do not require different treatment strategies. J Cardiovasc Pharmacol 1999; 33 Suppl.3: S1-7
Burns LA, Canter CE. Should -blockers be used for the treatment of pediatric patients with chronic heart failure? Pediatr Drugs 2002; 4 :771-778
Jefferies JL, Chang AC. The neurohormonal axis and biochemical markers of heart failure. Cardiol Young 2005; 15: 333-344
Rosenthal D , Chrisant MR , Edens E , International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. J Heart Lung Transplant. 2004; 23:1313-33.
Burch M , Siddiqi SA , Celermajer DS , Scott C , Bull C , Deanfield JE . Dilated cardiomyopathy in children: determinants of outcome. Br Heart J. 1994; 72: 246-50
Mason JW , O'Connell JB , Herskowitz A , et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995; 333:269-75. .
Braunwald E. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's principle of internal medicine. New York : McGraw-Hill, 2001
Katz AM: Heart failure pathophysiology, molecular biology and clinical management. Philadelphia , PA , Lippincott, Williams & Wilkins, 2000
Sipido KR, Eisner D. Something old, something new: changing views on the cellular mechanism of heart failure. Cardiovasc Research 2005; 68:167-174
Scoote M, Poole-Wilson PA, Williams AJ. The therapeutic potential of new insights into myocardial excitation-contraction coupling. Heart 2003; 89:371-376
Colucci WS, Braunwald E. Pathophysiology of heart failure. In: Braunwald A editor. Text book of cardiovascular medicine. 6 th ed. Philadelphia :WB Saunders Company, 2001:503-533
Burnett JC Jr, Costello-Boerrigter L, Boerrigter G. In: Mann DL editor. Heart failure - A companion to Braunwald's Heart Disease. Philadelphia :WB Saunders Company, 2004:279-289
Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 2002; 90: 520-530
Doust JA. Pietrzak E, Dobson A, Glasziou PR. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ 2005:330:625
Dhir M, Nagueh SF. Echocardiography and prognosis of heart failure. Curr Opin Cardiol 2002; 17:253-256
Tei C, Dujardin KS , Hodge DO, et al. Doppler echocardiographic index for assessment of global right ventricular function. J AM Soc Echocardiogr 1996; 9: 838-47
Myers J, Gullestad L. The role of exercise testing and gas-exchange in the prognostic assessment of patients with heart failure. Curr Opin Cardiol 1998; 13:145-155
Wu LA, Lapeyre AC, Cooper LT. Current role of endomyocardial biopsy in the management of dilated cardiomyopathy and myocarditis. Mayo Clin Proc 2001; 76:1030-8
Shaddy RE. In: Pediatric Heart failure: Medical management of chronic systolic left ventricular dysfunction in children. 2005 Taylor & Francis Group, pp589-619
Costello-Boerrigter LC, Boerrigter G, Burnett JC JR. Revisiting salt and water retention: new diuretics, aquaretics, and natriuretics. Med Clin North Am 2003; 87: 475-491
Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. JACC 2005; 46:1785-91
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone evaluation study investigators. NEJM 1999; 341 :709-717
Wasserstrom JA, Aistrup GL. Digitalis: new actions for an old drug. Am J Physiol Heart Circ Physiol 2005; 289:H1781-H1793
Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99:1265-1270
Adams KF, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002; 39:946-953
Garg R, Yusuf S. Overview of randomized trials on angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative group on angiotensin converting enzyme inhibitor trials. JAMA 1995; 273:1450-1456
McDonald KM, D'Aloia A, Parrish T, et al. Functional impact of an increase in ventricular mass after myocardial damage and its attenuation by converting enzyme inhibition. J Card Fail 1998; 4:203-212
Deswal A, MacLellan WR, Barger PM, Man DL. Emerging strategies in the treatment of chronic heart failure. Editor: DL Mann: Heart failure-A companion to Braunwald's heart disease. Philadelphia : WB Saunders Company, 2004: 637-647
Burns LA, Chrisant MK, Lamour JM, et al. Carvedilol as therapy in pediatric heart failure: an initial multicenter experience. J Pediatrics 2001;138:505-511
Shaddy RE, Tani LY, Gidding SS, et al. Beta-blocker treatment of dilated cardiomyopathy with congestive heart failure in children: A multi-institutional experience. J Heart Lung Transplant 1999;18:269-274
Laer S, Mir TS, Behn F, et al. Carvedilol therapy in pediatric patients with congestive heart failure: a study investigating clinical and pharmacokinetic parameters. Am Heart J 2002; 143:916-922
Azeka E, Franchini Ramires JA, Valler C, Alcides Bocchi E. Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment. J Am Coll Cardiol 2002; 40:2034-2038
Redha E, Martin JR, et al, Carvedilol for the treatment of congestive heart failure in children with cardiomyopathy (abstract). J Am Coll Cardiol 2002; 39:399A
Shaddy RE, Curtin EL, Sower B, et al. The pediatric randomized Carvedilol trial in children with heart failure: rationale and design. Am Heart J. 2002; 144: 383-389
Hoch M, Netz H: Heart failure in pediatric patients. Thorac Cardiovascular Surg 2005; 53:S129-134
Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002; 106: 2194-2199
de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362:316-322
Yancy CW. Treatment with B-type natriuretic peptide for chronic decompensated heart failure: insights learned from the follow-up serial infusion of nesiritide (FUSION) trial. Heart Fail Rev. 2004; 9:209-16.
Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. NEJM 2000; 343:246-253
Packer M Califf RM, Konstam MA, et al. Comparision of omaprilat and enalapril in patients with chronic heart failure: the Omaprilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002; 106 :920-926
Westheim G, Bostrom P, Christensen CC, et al. Hemodynamic and neuroendocrine effects for candoxatril and furosemide in mild stable chronic heart failure. J Am Coll Cardiol 1999; 34:329-332
O'Connor CM, Gattis WA , Gheorghiade M, et al. A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: The US ecadotril pilot safety study. Am Heart J 1999;138:1140-1148
Coletta AP, Cleland JGF. Clinical trials update: highlights of the scientific sessions of the XXIII Congress of the European Society of Cardiology- WARIS II, ESCAMI, PAFAC, RITZ-I and TIME. Eur J Heart failure 2001; 3:747-750
Givertz MM, Colucci WS, Lejemtel TH et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilatation in patients with chronic heart failure. Circulation 2000; 101:2922-2927
Nawarskas J, Anderson J. Levosimendan: a unique approach to the treatment of heart failure. Heart Dis 2002; 4:265-71
Follath F, Cleland J, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomized double blind trial. Lancet 2002; 360:196-202
Bohm M, Morano I, Pieske B, et al. Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium. Circ Res 1991; 68:689-701
Bosker B, Torre-Amitone G, Warren MS et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulations 2001; 103:1044-1047
Mou S, Haudek S, Lequier L, et al. Myocardial inflammatory activation in children with congenital heart disease. Crit Care Med 2002; 30:827-832
Pulley MK. Etanercept. Immunex. Curr Opin. Investig. Drugs. 2001;2:1725-1731
Infliximab (Remicade) package insert. Malvern, Penn, Centocor, Inc, 2003
Khatta M, Alexander BS, Krichten CM, et al. The effect of coenzyme Q10 in patients with congestive heart failure. Ann Intern Med 2000; 132:636-640
Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatinine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997; 96 :2190-2196
Lopaschuk GD, Belke DD, Gamble J, et al. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994; 1213 : 263-276
Sambandam N, Lopaschuk GD, Brownsey RW, et al. Energy metabolism in the hypertrophied heart. Heart Fail Rev 2002; 7 :161-173
Sack MN, Rader TA, Park S, et al. Fatty acid oxidation enzyme gene expression is down regulated in the failing heart. Circulation 1996; 94 :2837-2842
Lehman JJ, Kelly DP. Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev 2002; 7 :175-185
Shamim W, Francis DP, Yousufudin M et al. Intraventricular conduction delay: A prognostic marker in chronic heart failure. Int J Cardiol 1999; 70:171-178
Brecker SJ, Xiao HB, Sparrow J, et al. Effects of dual chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 1992; 340:1308-1312
Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. NEJM 2002; 346:1845-1853
Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: A meta-analysis of randomized controlled trials. JAMA 2003; 289:730-740
Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. NEJM 1991; 324:781-788
Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter autonomic defibrillator implantation trial investigators. NEJM 1996; 335 :1933-1940
Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter unsustained tachycardia trial investigators. NEJM 1999; 341 :1882-1890
Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. NEJM 2002; 346 :877-883
Fricker FJ, Addonizio L, Bernstein D, et al. Heart transplantation in children: Indications. Pediatr Transplantation 1999; 3:333-342
Das BB, Taylor AL, Boucek MM, Wolfe RW, Yetman AT. Exercise capacity in pediatric heart transplant candidates: Is there any role for the 14 milliliter / kilogram / min guideline? Pediatric Cardiol 2005 Dec 27 [Epub ahead of print]
Gajarski RJ, Towbin JA, Bricker JT, et al. Intermediate follow-up of pediatric heart transplant recipients with elevated pulmonary vascular resistance index. J Am Coll Cardiol 1994; 23:1682
Young J, Naftel D, Bourge R, et al. Matching the heart donor and heart transplant recipient. Clues for a successful expansion of the donor pool: a multivariable, multi-institutional report. J Heart Lung Transplant 1994; 13:353-365
Murali S, Kormos RL, Uretsky BF, et al. Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplant. Am Heart J 1993; 126:896-904
Frazier OH, Myers TJ. Left ventricular assist system as a bridge to myocardial recovery. Ann Thorac Surg 1999; 68:734-741
Hetzer R, Muller JH, Weng Y, et al. Bridging-to-recovery. Ann Thorac Surg 2001; 71:S109-S113
Westaby S, Coats AJ. Mechanical bridge to myocardial recovery. Eur Heart J 1998; 19:541-547
Matsuda H, Taenaka Y, Ohkubo N, et al. Use of paracorporeal pneumatic ventricular assist device for postoperative cardiogenic shock in two children with complex cardiac lesions. Artif Organs 1988; 12:423-430
Ishino K, Loebe M, Uhlemann F, et al. Circulatory support with paracorporeal pneumatic ventricular assist device (VAD) in infants and children. Eur J Cardiothorac Surg 1997; 11:965-972
Weyand M, Keceicioglu D, Kehl HG, et al. Neonatal mechanical bridging to total orthotopic heart transplantation. Ann Thorac Surg 1998; 66:519-522
Reinhartz O, Stiller B, Eilers R, et al. Current clinical status of pulsatile pediatric circulatory support. ASAIO L 2002; 48:455-459
Ashton RC, Oz MC, Michler RE, et al. Left ventricular assist device options in pediatric patients. ASAIO J 1995; 41:M277-M280
Marelli D, Desrosiers C, el Alfy M, et al. Cell transplantation for myocardial repair: An experimental approach. Vell Transplant 1992;1:383-390
Li RK, Jia ZQ, Weisel RD , et al. Smooth muscle cell transplantation into myocardial scar tissue improves heart function. J Mol Cell Cardiol 1999; 31:513-522
Klug MG, Soonpaa MH, Koh GY, et al. Genetically selected cardiomyocytes from differentiating embryonic stem cells from stable intracardiac grafts. J clin Invest 1996; 98:216-224
Wang JS, Shum-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty: Feasibility and potential clinical advantages. J Thorac Cardiovasc Surg 2000; 120:999-1005
Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410:701-705
Pagani FD, DerSimonian H, Zawadzka A, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003; 41:879-888
Hagege AA, Carrion C, Menasche P, et al. Viability and differentiation of autologous skeletal myoblasts in ischaemic cardiomyopathy. Lancet 2003; 361:491-492
Last updated on 01-01-2007 Vol 4 Issue 1 Art # 1
How to cite this url
Bibhuti B Das, Solinger R. Emerging Therapies For Chronic Heart Failure In Children And Young Adults.Pediatric Oncall [serial online] 2007 [cited 2007 January 1];4. Art # 1. Available from: