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EMERGING THERAPIES FOR CHRONIC HEART FAILURE IN CHILDREN

AND YOUNG ADULTS

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.

Keywords : pediatric heart failure, left ventricular remodeling, carvedilol, nesiritide, levosimendan, cardiac

resynchronization therapy, ventricular assist device, pediatric heart transplantation

Introduction: 

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 adultsand (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.

Etiology : 

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, primarypulmonary 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 bloodat 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 inventricular cardiac muscle fibers leading to excessive expansion of ventricles in diastole as seen in left to rightshunt, mitral regurgitation and complete heart block; (2) abnormally high afterload as in hypertension, coarctationof the aorta and aortic stenosis; (3) impaired myocardial contractility as in myopathy, myocarditis;

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and (4) inadequate diastolic filling as in hypertrophic or restrictive cardiomyopathy, constrictive pericarditis andtachyarrhythmias. 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 samecompensatory 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. Butwhen sympathetic action is undeterred, tachycardia and peripheral vasoconstriction (increased afterload)leads to substantial increase in cardiac work and myocardial oxygen consumption. Furthermore, at thecellular level, compensatory gain in cardiac excitation-contraction coupling mediated by sympatheticstimulation ultimately become unsuccessful as evidenced by unwanted diastolic leak of sarcoplasmicreticulum calcium leading to depletion of intracellular calcium and loss of contractility. (14-15 ) 

  The compensatory stimulation of renin-angiotensin-aldosterone system causes vasoconstriction and renalretention of salt and water which increases diastolic filling pressure and increase myocardial contractilitythrough Frank-Starling mechanism. (16) But when these effects are excessive, it causes systemic andpulmonary venous congestion and increases after load. In addition, renin-angiotensin-aldosterone systemis responsible in mediating renal hyporesponsiveness to the natriuretic peptides, which facilitates

progression of heart failure . (17) The compensatory ventricular hypertrophy initiated and regulated bymany of the signaling molecules that mediate the neurohormonal responses in the failing heart providesmore contractile elements. However, maladaptive hypertrophy ultimately results in myocardial cell deathand 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 tonecrosis, fibrosis and further dysfunction. (13-14) The extracellular matrix remodeling is promoted byneurohormonal activation and activation of pro-inflammatory cytokines. Increase plasma levels of matrixmetalloproteinases are associated with severe heart failure and probably reflect progressiveremodeling. (18) There is up-regulation of myocardial matrix metalloproteinases associated withdecreased fibrillar collagen cross-link formation in patients with chronic systolic heart failure withcardiomyopathic ventricles.

Clinical manifestations : 

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. Exerciseintolerance is an important feature of heart failure in older children and young adults.

Laboratory studies : 

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 . Braintype 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.

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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 beenextrapolated from trials in adults. Although there is good rationale for doing this, there are significant differencesbetween the substrate for left ventricle dysfunction between children and adults. (24) In general, pharmacotherapyfor chronic compensated heart failure has three goals: the rapid relief of symptoms, slowing of thepathophysiological process involved in left ventricle remodeling and increasing patient survival. Despite thestandard pharmacotherapy ( Table-1 ), some children and young adults with heart failure remain in a chronicdecompensated state. These patients require intravenous inotropes and vasodilator medications. Some of thesepatients with end-stage heart failure become inotrope-dependent, and are candidates for newer therapies includingbut not limited to ventricular assist device as a bridge to transplantation or recovery. Evidence-based medicine formanagement of pediatric heart failure does not exist at this time. Until large, multicenter trials of children withheart failure are performed, the best course for pediatric cardiologists is to follow the adult literature, cautiouslyintroduce accepted therapies, and follow patients closely.

Diuretics :

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 nolong-term benefits and do not prevent the disease progression in chronic heart failure. Loop diuretics arepreferable to most other diuretics secondary to their effectiveness and potency. Combination therapy has beenshown to be more effective than monotherapy with one class at escalating dose because sequential sites in thenephron can be blocked. New diuretics called aquaretic which are vasopressin receptor antagonists areavailable. (25) Two vasopressin antagonists currently being used in clinical trials are tolvaptan (vasopressinreceptor-2 antagonist) and conivaptan (combined vasopressin receptor-1a and -2 antagonists). (26) The potentialvalue of these agents is the fact that they cause elimination of water, without the loss of electrolytes, thuspotentially negating the need for frequent follow-up of serum electrolytes levels.

Aldosterone antagonist: 

Aldosterone antagonists (spironolactone and eplerenone) have been shown to reduce mortality in adults with heartfailure. (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 increasedmyocardial fibrosis, increased angiotensin converting enzyme and endothelin activity, increased free radicalproduction, and decreased adrenal nitric oxide. Low dose spironolactone is considered to be an inhibitor of renin-angiotensin-aldosterone axis, rather than diuretic.

Digoxin : 

Digoxin inhibits the sarcolemmal sodium-potassium-adenosine triphophatase pump which results in increasedintracellular sodium and subsequent increase in intracellular calcium through inhibition of sodium-calciumexchanger. This increase in intracellular calcium results in increased contractility. Other beneficial effects of digoxininclude reduction of sympathetic tone and norepinephrine levels. Recent observations suggest that digitalis mayhave additional effects on cardiac cell function in both the short and long term that include intracellular effects,interactions with specific sodium-potassium-adenosine triphophatase isoforms in different cellular locations, effectson intracellular (including nuclear) signaling, and long-term regulation of intracellular ionic balances throughcirculating 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 inchildren with heart failure is unknown.

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers :

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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.