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

Metabolic therapy

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 than 120 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, anti-arrhythmic 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 transplantation:

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 longterm ventricular assist device in children should be more useful and myocardial recovery should be better due to the plasticity 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 longterm 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.