Di Filippo Oxygen delivery is the product of oxygen content in the blood and cardiac output. Oxygen content is the arterial oxygen satu- ration and cardiac output is the product of heart rate and stroke volume; the latter is a result of preload, afterload, and contractility conditions of the heart. Any alteration of one (or more) these three components may lead to the occurrence of HF. Incidence The incidence of HF in children depends on the underlying cardiac disease and the age of the patient. The annual inci- dence of HF due to cardiomopathy in the ﬁrst year of life is as high as 4 cases per 100,000 live births (O’Laughlin 1999; Kay et al 2001). It seems to be 16 times as high in patients less than 1 year old than in those more than 1 year. The prevalence of HF among patients with structural heart defects is unknown. Failure of the systemic ventricle may occur in patients with systemic right ventricle who had undergone Mustard or Senning operation (atrial bafﬂe switch correction of transposition of the great vessels), or in those with long-term Fontan-type palliation and functionally single ventricle (total cavo-pulmonary derivation). Causes of HF in children The causes of HF in children are very heterogeneous (Kay et al 2001). Congestive HF due to left to right shunts and/or left heart outﬂow tract obstruction is mostly accessible to pal- liative or reparative surgery (Auslender and Artman 2000). Cardiomyopathy is the main cause of left ventricle fail- ure. In these cases, myocardial dysfunction may be related to myocarditis or anthracycline toxicity or even metabolic diseases, or may be idiopathic and sometimes from genetic inheritance. Of highest concern are the cases with chronic HF due to dysfunction of the systemic functional ventricle in the con- text of congenital heart disease, either left ventricle or right ventricle or single ventricle. Failure of the systemic ventricle due to congenital structural abnormalities of the heart is an unique feature of the pediatric HF population. Not only left ventricle, but also systemic right or single ventricle dysfunc- tion may be involved in the mechanisms of HF in children. Failure of reparative surgery, of Fontan-type single ventricle physiology, or of an overworked systemic right ventricle are crucial issues to address (Kay et al 2001). Pathophysiological mechanisms of HF in children Several mechanisms are activated to compensate for impaired cardiac output. HF results from inadequate tissue oxygen 848 delivery and develops when the compensatory mechanisms are overhelmed or as a consequence of these mechanisms (O’Laughlin MP 1999; Francis 2001; Kay et al 2001). The adaptative mechanisms aim to maintain perfusion of vital organs through: 1) maintenance of systemic pressure by vasoconstriction, 2) restoration of cardiac output by increasing heart rate, contractility, and extracellular volume (Figure 1). The neurohormonal activation is thought to be the main adaptative mechanism in HF, but it aggravates the HF through detrimental consequences of activation (Hoch and Netz 2005). In this setting, the activation of the renin-angiotensin system stimulates aldosterone and angiotensin II production. Subsequent salt and water retention results in increased pre- load and angiotensin-induced peripheral vasoconstriction in increased afterload, in order to compensate for low cardiac output. Volume expansion is effective because increased venous return results in elevation of end-diastolic volume. The Franck Starling mechanism subsequently leads to dilata- tion of the ventricular cavity which aims to enhance cardiac stroke volume. Additional activation of the sympathic ner- vous system exacerbates the production of catecholamines and the stimulation of cardiac beta-receptors. Increases in myocardial contractility, heart rate, and wall stress are the main consequences of activation of the sympathetic nervous system. Sustained cardiac adrenergic activation results in desensitization of beta-adrenergic signal transduction mechanisms, downregulation of beta-receptor, and direct damage to cardiac myocytes. Failing hearts show decreased catecholamine sensitivity and impaired beta-adrenergic- receptor density (Hoch and Netz 2005). Other mechanisms combine to aggravate the deleterious consequences of neurohormonal activation, ie: – Besides its diuretic effect, aldosterone may enhance inter- stitial collagen and cause ﬁbrosis in long-term HF, leading to alteration of the diastolic function of the heart. – Angiotensin II is thought to induce myocyte apoptose. – Abnormal gene expression leads to change in the actin, myosin, and collagen isoforms. – Lastly, intracellular calcium release may inﬂuence sys- tolic and also diastolic function of the heart. The combination of the above mechanisms results in remodeling of the cardiac structures, through dilation of the cavities, hypertrophy, cell death, decrease in capillary density, and mitochondrial deﬁciency. More recent literature provides new insight about the mechanisms of HF. In particular, pulmonary and systemic congestion seem to be important predictors of both mortality Therapeutics and Clinical Risk Management 2007:3(5)