Address for correspondence : Bibhuti B Das, MD, Division of Pediatric Cardiology, Suite # 334, University of Louisville, Louisville, KY 40202, USA.E-mail: bdas99@hotmail.com

Beta-blocker therapy :

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.

Nesiritide

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.

Vasopeptidase inhibitors :

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. Non-selective endothelin receptor antagonists such as bosentan, tezosentan and ondansetron 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)

Calcium-sensitizing agents :

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 loading 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)

Cytokine antagonists :

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