Hypertrophic Cardiomyopathy in Infants and Children

The definition and classification of the cardiomyopathies has been traditionally a complex and quite variable subject. In 2006, the American Heart Association issued a scientific statement elaborated by a task force of experts that contemplated the important development of molecular genetics in recent years, to explain the etiology of the diseases of cardiac muscle, or cardiomyopathies, previously considered idiopathic (B.J. Maron et al., 2006a). The document stated that “Cardiomyopathies are an heterogeneous group of myocardial diseases associated with mechanical and/or electrical dysfunction that usually, but not always, exhibit inappropriate ventricular hypertrophy or dilation, and are originated by a variety of causes, frequently genetic. Cardiomyopathies involve just the heart or are part of systemic disorders that often lead to cardiovascular death or heart failure related disability”. Myocardial damage secondary to coronary atherosclerosis, heart valve disease, congenital heart disease, and systemic hypertension, is excluded from this definition. Primary or metastatic cardiac tumors and diseases primarily affecting the endocardium with minimal or absent myocardial damage neither are included. The document also discourages the use of the classical terminologies hypertrophic, dilated, and restrictive cardiomyopathies because they have overlapping features and often mutate from one type to another during the course of the disease. Cardiomyopathies are then classified into 2 groups, primary when there is only heart involvement, and secondary if the heart is affected by systemic diseases with multiorganic involvement. (Table 1) Primary cardiomyopathies are divided into genetic, acquired, and mixed (genetic and acquired).


Introduction
The definition and classification of the cardiomyopathies has been traditionally a complex and quite variable subject. In 2006, the American Heart Association issued a scientific statement elaborated by a task force of experts that contemplated the important development of molecular genetics in recent years, to explain the etiology of the diseases of cardiac muscle, or cardiomyopathies, previously considered idiopathic (B.J. Maron et al., 2006a). The document stated that "Cardiomyopathies are an heterogeneous group of myocardial diseases associated with mechanical and/or electrical dysfunction that usually, but not always, exhibit inappropriate ventricular hypertrophy or dilation, and are originated by a variety of causes, frequently genetic. Cardiomyopathies involve just the heart or are part of systemic disorders that often lead to cardiovascular death or heart failure related disability". Myocardial damage secondary to coronary atherosclerosis, heart valve disease, congenital heart disease, and systemic hypertension, is excluded from this definition. Primary or metastatic cardiac tumors and diseases primarily affecting the endocardium with minimal or absent myocardial damage neither are included. The document also discourages the use of the classical terminologies hypertrophic, dilated, and restrictive cardiomyopathies because they have overlapping features and often mutate from one type to another during the course of the disease. Cardiomyopathies are then classified into 2 groups, primary when there is only heart involvement, and secondary if the heart is affected by systemic diseases with multiorganic involvement. (Table 1) Primary cardiomyopathies are divided into genetic, acquired, and mixed (genetic and acquired).

Classification
Though hypertrophic cardiomyopathy was first recognized by Liouville in France in 1869, (Liouville, 1869, as cited in Marian, 2007), it was not until the 1950's that was rediscovered in Britain by Brock and Teare (Brock & Fleming, 1956;Teare, 1958). Initial reports emphasized the presence of left ventricular outflow tract obstruction until it was realized that this could be absent (B. J. ). Since then, two main types of hypertrophic cardiomyopathy were distinguished, with or without obstruction. Nowadays, we know that hypertrophic cardiomyopathy, is the most frequent monogenic disorder in cardiology and the commonest cause of sudden death in youngsters in either form of presentation (J. Seidman & C. Seidman, 2001). Regardless of the presence or absence of obstruction, hypertrophic cardiomyopathy is classified into two main groups, familial and non-familial. (Table 3) The latter comprises 4 subgroups: hypertrophic cardiomyopathy associated with obesity, infants born to diabetic mothers, athlete's heart, and amyloidosis. This chapter will mainly address the familial forms of hypertrophic cardiomyopathy also composed of 4 subgroups: sarcomeric, and 3 others in association with malformation syndromes, inborn errors of metabolism, and neuromuscular disorders (Elliot et al., 2008). The sarcomeric forms are the most frequent and have an autosomal dominant inheritance. They are caused by missence mutations of genes encoding the contractile proteins of the sarcomere. A mutation involves the change of a DNA base for another resulting in the replacement of an aminoacid in a polypeptide for another. Though readable, the meaning (sense) of the genetic message is changed. Considerable genetic and phenotypic heterogeneity is found in hypertrophic cardiomyopathy. In other words, different gene mutations may cause similar phenotypes or on the contrary, the same gene may result in dissimilar ones. The presence of modifying genes, like that encoding angiotensin II, environmental influences, gender, and associated conditions might explain some of these dissimilarities (Alcalai et al., 2008). About 20 genes carrying a great number of mutations have already been identified in hypertrophic cardiomyopathy (Kim et al., 2011). (Table 4) However, just 3 of them, beta-myosin heavy chain (MYH7), myosin binding protein C (MYBPC3), and troponin T (TNNT2) are responsible for almost 75% of the cases, thence, the remaining are rare. The genes involved in pediatric hypertrophic cardiomyopathy have a similar frequency and distribution as in adult patients (Kaski et al., 2009).

Sarcomeric
Associated with obesity Associated with malformation syndromes Infants born to diabetic mothers Associated with inborn errors of metabolism Athlete's heart Associated with neuromuscular disorders Amyloidosis

Prevalence
The estimated prevalence of hypertrophic cardiomyopathy in the adult population as assessed by echocardiographic screening is 1:500 (B.J. Maron et al., 1995a

Macroscopic findings
The gross anatomy generally shows severe left ventricular hypertrophy and small cavity size. (Fig. 1) The hypertrophy mainly involves the ventricular septum, and for this reason, one of the early denominations of the disease was asymmetric septal hypertrophy (Henry et al., 1973). Notwithstanding, hypertrophy may occur symmetrically or affect other segments like the posterior wall, and the apical or middle sections of the left ventricle (Falicov & Resnekov, 1977;Louie & Maron, 1987;Minami et al., 2011;Yamaguchi et al., 1979). Midventricular obstructive hypertrophic cardiomyopathy is more frequent in Asians with a prevalence of around 10% in tertiary centers and carries a higher risk for adverse events (B.J. Maron et al., 2003a;Minami et al., 2011). Patients with apical involvement are less commonly genotype positive than those with the more frequent variants of the disease but the affected genes are usually the same frequently found in the other patients (MYBPC3 and MYH7) (Gruner et al., 2011). In infants and children, the right ventricle can also be involved (Biagini et al., 2005).Almost 5% of patients with hypertrophic cardiomyopathy evolve to end stage dilated cardiomyopathy with extensive fibrosis, myocardial wall thinning and cavity dilation (Harris et al., 2006). The left atrium is enlarged as a consequence of the elevated left ventricular end diastolic pressure caused by diastolic dysfunction and mitral regurgitation secondary to left ventricular outflow tract obstruction or associated mitral valve anomalies (Klues et al., 1992). The physiopathology of mitral insufficiency in hypertrophic obstructive cardiomyopathy was initially attributed to the Venturi effect produced by systolic flow acceleration in the left ventricular outflow tract dragging the anterior mitral valve leaflet towards the ventricular septum causing both obstruction and insufficiency (Grigg et al., 1992;Panza et al., 1992;Shah et al., 1969Shah et al., & 1971. A subsequent echocardiographic and Doppler study suggested instead, that the mitral valve leaflets are protruding into a narrow left ventricular outflow tract at the onset of ejection causing that rapid forward flow becomes the dominant force that pushes the leaflets toward the septum being the immediate cause of obstruction. After the onset of obstruction the leaflets are forced against the septum by the pressure difference across the orifice. The raising gradient leads to a smaller orifice and a higher gradient (Sherrid et al., 1993). The systolic anterior motion of the mitral leaflets precludes the proper sealing of the mitral orifice generating mild to moderate mitral regurgitation (M. Maron et al., 2011). The mitral valve in these patients shows alterations in size and shape which are thought to be primary abnormalities of the disease. The main changes are elongation and increase of the leaflet area usually not symmetrical. The size of the left ventricular outflow, the hyperdynamic contraction and the alterations of the mitral valve are the causes of the obstruction.

Microscopy
The distinct feature of the microscopic examination of the myocardium is hypertrophy and marked disarray (greater than 5% of the myocardial tissue) of individual and grouped myocardiocytes (myofibers) that instead of being normally aligned are interspersed in different directions forming whorls around areas of fibrosis. Cells and fibers lose their normal parallelism and can even be found almost perpendicular to each other. (Fig. 2) The disarray also includes the intracellular myofibrils. Other findings include increased connective tissue leading to interstitial fibrosis and thickening of the microvascular coronary artery walls with luminal reduction resulting in ischemia and fibrosis (Ferrans et al., 1972). Fibrosis and scar replacement of necrosed cells is more evident in areas with greater hypertrophy. Initially, it was postulated that the mechanism for the disarray and hypertrophy was caused by the increased effort of the myocytes to compensate the inefficient contractility of the affected sarcomere proteins. This would activate the insulin and tissue growth factors and angiotensin II resulting in the myocardial changes (J. Seidman & C. Seidman, 2001). Further experimental animal investigations and studies of hypertrophic cardiomyopathy mutations in man, by the same authors, found instead that the mutated sarcomeres had in fact increased function. It was then hypothesized that they would activate signals for hypertrophic remodeling. Abnormalities in calcium signaling were encountered leading to necrosis and replacement fibrosis producing diastolic dysfunction, a main feature of hypertrophic cardiomyopathy (C. Seidman & J. Seidman, 2011). An investigation by the same group, also found that a profibrotic marker like serum procollagen is significantly higher in patients with full blown hypertrophic cardiomyopathy and mutation carriers, with a still not developed phenotype, than in controls, pointing to increase collagen synthesis and fibrosis. Late gadolinium enhancement studies are positive when hypertrophy is already present (Ho et al., 2010). The myocardial disarray, interstitial fibrosis, and ischemia are also the substrate for the occurrence of arrhythmias.

Phenocopies
Patients with nonsarcomeric hypertrophic cardiomyopathy are considered to be phenocopies (Table 5), and might have the same pathologic findings as has been reported in some malformation syndromes or neuromuscular disorders like Noonan's syndrome and Friedreich's ataxia (Burch et al., 1992;Kawai et al., 2000). However, this is not the case for inborn errors of metabolism like glycogen storage disease where the gross anatomy resembles hypertrophic cardiomyopathy but microscopic examination shows the glycogen deposits in the myocytes without disarray. (Fig. 3) It should be noted that the present definition of phenocopy, according to the Webster's New World Medical Dictionary in its second acception is: "A person who has an environmental condition that mimics a condition that is produced by a gene". Since the examples just mentioned are genetic in origin, the term phenocopy could be inappropriate but is how these entities have been named for a long time.

Clinical findings
Aside from the genetic and phenotypic heterogeneity already mentioned in hypertrophic cardiomyopathy, the age, form of presentation, and outcome, are also quite diverse. The age of the patient at presentation is a determinant of prognosis (Colan et al., 2007). Newborn and infants are more likely to be referred for congestive heart failure while older children are usually asymptomatic at the time of diagnosis and the consultation is requested because of the presence of a heart murmur, cardiomegaly casually detected on a chest x-ray, or electrocardiographic abnormalities (Bruno et al., 2002). Initially, asymptomatic patients may go on without symptoms for a long period of time until they begin experiencing fatigue and dyspnea, and less frequently, palpitations, chest pain, and syncope or sudden death which might be the first symptom ever. Another cause of referral is the investigation of cardiac involvement in patients with conditions known to be associated with hypertrophic cardiomyopathy like the malformation syndromes, inborn errors of metabolism or neuromuscular disorders. However, in other circumstances, the associated disease may have been unnoticed and the cardiomyopathy is discovered first. The presence of physical findings suggesting an association then prompts referral to the geneticist (Alday & Moreyra, 1984). With regard to the physical examination itself, in hypertrophic obstructive cardiomyopathy, the peripheral pulses may rise and descend rapidly. When considerable cardiac enlargement is present, a precordial bulge and outward displacement of the point of maximal impulse are usually found. A double apical impulse caused by a 4 th heart sound is often noted. A harsh, blowing systolic murmur with varying intensity, related to the degree of obstruction and mitral regurgitation, can be listened along the left sternal border and at the apex. A distinctive feature of these murmurs is the variability seen with maneuvers that increase or reduce the obstruction intensifying or decreasing their intensity (Moreyra et al, 1972). (Fig. 4) Patients with non obstructive hypertrophic cardiomyopathy may also have ejection systolic murmurs along the left sternal border though softer than when there is left ventricular outflow obstruction. An ambulatory electrocardiographic study performed in infants, children and adolescents with hypertrophic cardiomyopathy concluded that arrhythmias occur rarely before adolescence. However, from then on, prevalence of nonsustained ventricular tachycardia is as high as 18%. It is also worth mentioning that absence of arrhythmias is not synonymous of low risk for sudden death (

Radiology
The chest x-ray is usually normal in early stages of the disease but following the pubertal growth spurt shows cardiomegaly at the expense of the left sided chambers (B.J. Maron et al., 1986). (Fig. 5) The same is true for patients evolving to end-stage hypertrophic cardiomyopathy (Biagini et al., 2005). Finally, infants with severe heart failure nearly always have considerable cardiac enlargement at presentation. Pulmonary venous hypertension secondary to elevation of the left ventricular end diastolic pressure is reflected by the well known resultant pulmonary vascular changes.

Electrocardiography and allied techniques
The electrocardiogram is usually abnormal in almost all patients with hypertrophic cardiomyopathy. (Panza & Maron, 1989) The electrocardiographic abnormality, even a slight one, may precede the echocardiographic findings showing left ventricular hypertrophy in family members carrying the genotype of probands with hypertrophic cardiomyopathy. Therefore, this should be kept on mind when screening relatives of hypertrophic cardiomyopathy patients (Gregor et al., 1989). Left atrial enlargement and left ventricular hypertrophy by voltage criteria usually associated with ST-T abnormalities are seen. (Fig. 6) Younger patients may have combined ventricular or isolated right ventricular hypertrophy with a rightwards QRS axis.    . The wall thickness echocardiographic criteria for the diagnosis of hypertrophic cardiomyopathy was set at greater than 2 SD above the mean for the body surface area of the population for a localized or general myocardial hypertrophy (Grenier et al., 2000). When in the absence of pulmonary valve stenosis the right ventricular wall thickness exceeds 4 mm the right ventricle is considered to be involved too (Nugent et al., 2005). Left ventricular hypertrophy is most frequently asymmetric with greater involvement of the interventricular septum than the rest of the walls, though it can also be concentric. (Fig. 9 -11) More rarely, it is localized in the anterior wall, the apex, or in the mid left ventricle (M. , Minami et al., 2011. The mid ventricular obstruction may lead to the development of an apical left ventricular aneurysm. (Fig. 12) In younger children the right ventricle may also be affected (Biagini et al., 2005). As a consequence of mitral insufficiency and/or diastolic dysfunction, there is left atrial enlargement. The systolic anterior movement of the mitral valve contacting the ventricular septum that causes left ventricular outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy is readily seen (B.J. Maron et al., 2003). Color flow mapping allows detection of the site of obstruction. (Fig. 13) The gradient across the outflow tract is estimated by continuous wave Doppler that also allows assessment of the mitral regurgitation severity. (Fig. 14) Transesophageal echocardiography is more sensitive than transthoracic studies for evaluation of primary mitral valve anomalies producing mitral incompetence (Kuhl & Hanrath, 2004

Computed tomography and magnetic resonance imaging
Cardiac computed tomography and magnetic resonance imaging yield superior anatomic data than echocardiography since they allow better definition of the anterolateral wall and tip of the left ventricle and the right ventricle. However, these procedures are more costly and the former exposes the patient to radiation (M. Maron

Cardiac catheterization and cineangiocardiography
We owe to cardiac catheterization and cineangiocardiography the initial understanding of the physiopathology of hypertrophic cardiomyopathy shortly after its rediscovery about half a century ago (Braunwald et al., 1964;Wigle, Auger & Marquis, 1967). These techniques were then considered the gold standard for the diagnosis of hypertrophic obstructive cardiomyopathy. (Fig. 18) With the advent of the just discussed noninvasive imaging techniques like Doppler-echocardiography, computed tomography, and magnetic resonance imaging, this invasive procedure is no longer necessary for diagnostic purposes. Nowadays, this method is only used before planned surgical treatment or percutaneous interventions for septal reduction.

Arrhythmias
Supraventricular and nonsustained ventricular tachycardias, were found in almost a third of pediatric and adolescent patients with hypertrophic cardiomyopathy studied by ambulatory electrocardiography (McKenna, et al., 1988). However, their outcome after a mean follow-up of 3 years was rather benign. In a study from our group, a quarter of the patients had symptomatic atrial or ventricular tachycardia. Three out of 7 died suddenly during followup (Bruno et al., 2002). Rarely, 3 rd degree atrioventricular block is found in children with hypertrophic cardiomyopathy. They could present with near syncope or syncopal attacks as the 1 st manifestation of the disease (Rosen et al., 1997).

Evolving phenotype
Children with hypertrophic cardiomyopathy may evolve to dilated or restrictive cardiomyopathy phenotypes in 5% of the cases. In both circumstances they have a dimmer prognosis and become candidates for heart transplantation (Biagini et al., 2005;Denfield et al., 1997;Shirani et al., 1993).

Differential diagnosis
The most important differential diagnosis is with the athlete's heart and is sometimes somewhat difficult to make. Highly trained competitive athletes may have electrocardiographic abnormalities that resemble those of hypertrophic cardiomyopathy. As in this situation, the left ventricle is hypertrophied but the wall thickness as determined by echocardiography does not exceed 15 mm in diameter and the hypertrophy is symmetrical. The left ventricular cavity is dilated and the ejection fraction is normal while hypertrophic cardiomyopathy is frequently accompanied by unusual distribution of hypertrophy, the left ventricle is smaller in size (<4.5 cm) and the ejection fraction is higher than normal. Furthermore, left ventricular diastolic function is normal in young athletes but is always impaired in hypertrophic cardiomyopathy (B.J. Maron, Spirito & Pelliccia, 1995b). Tissue Doppler studies has also been very useful to distinguish those patients in the "grey zone" (Cardim et al., 2003). When still in doubt regarding the diagnosis, cessation of physical activities usually results in regression of the left ventricular mass in a few weeks' time (B.J. Maron et al.., 1993). Genetic screening might be useful when they are positive for a mutation which occurs in up to 70% of patients with hypertrophic cardiomyopathy. On the contrary, a negative test does not exclude the possibility of a mutation still not discovered.  (Colan et al., 2007). These variants are called phenocopies and are listed in Table 5. They are classified as malformation syndromes, inborn errors of metabolism, and neuromuscular disorders and each group numbers about one third of the total.

Malformation syndromes 9.1.1 Noonan's and LEOPARD syndromes
The most common malformation syndromes associated with hypertrophic cardiomyopathy included in the European Society of Cardiology classification of familial hypertrophic cardiomyopathy, are Noonan's syndrome and its allelic variant LEOPARD syndrome, acronym for lentiginosis, electrocardiographic anomalies, ocular hypertelorism, pulmonic stenosis, abnormal male genitalia, retardation of growth, and deafness. The prevalence of Noonan,s syndrome, initially described as the Turner phenotype with normal karyotype (Noonan, 1968), is estimated in 1:2,000 births (Nora et al., 1974). (Fig. 19) It is inherited as an autosomic dominant form and nearly 80% have congenital heart disease, most frequently pulmonic valve and arterial stenoses, and atrial and ventricular septal defects. The introduction of echocardiography as a diagnostic tool, allowed the recognition of an association with hypertrophic cardiomyopathy in almost a quarter of patients (Nora et al., (1975). In the Australian epidemiologic study of childhood cardiomyopathies, 28% of 80 patients with hypertrophic cardiomyopathy had Noonan's syndrome (Nugent et al., 2005). These patients presented earlier and had more frequent biventricular involvement. However, they did not find greater adverse events rate than in sarcomeric hypertrophic cardiomyopathy. In about 40-50% of patients a mutation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11) is found (Type 1 Noonan's syndrome), but this is present in 90% of LEOPARD patients (Sznajer et al., 2007;Tartaglia et al., 2001). This gene controls a series of developmental processes, among them the genesis of semilunar valves. The mutation is then mainly present in patients with heart defects but not in those with hypertrophic cardiomyopathy.

Related conditions
Some related genetic conditions to Noonan's syndrome like the Costello syndrome, the cardiofaciocutaneous syndrome, and palmo-plantar hyperkeratosis with woolly hair may also be associated with hypertrophic cardiomyopathy (Peirone et al., 2005, Roberts et al., 2006.

Inborn errors of metabolism 9.2.1 Pompe's disease
Pompe's disease or type II glycogen storage disease is an autosomal recessive inherited disorder caused by absence of the acid alpha-glucosidase enzyme (GAA) preventing the normal degradation of glycogen in the cardiac myocyte (Hers, 1963). There is an infantile type with massive cardiac enlargement as seen in hypertrophic cardiomyopathy with obstruction leading to congestive heart failure and early death (Ehlers et al., 1962). A typical electrocardiogram is shown in Fig. 20. Late onset Pompe's disease with a better outcome has also been described (Winkle et al., 2005). Enzyme replacement therapy is now available for treatment of GAA deficiency. Fig. 19. A. Phenotype of a 10-year-old girl with Noonan's syndrome and hypertrophic cardiomyopathy. There is short stature, peculiar face, eyelid ptosis with downward slant, ocular and mammillar hypertelorism, low set ears, pterigium colli, and a prominent chest. B.
Ten-year-old girl with LEOPARD syndrome. The multiple lentigines and hypertrophic obstructive cardiomyopathy became apparent long after she had been operated on for severe pulmonary valve stenosis when she was 6-month old (Reproduced with permission from Am Heart J, 1984; Vol.108, pp. 996-1000).

Other glycogen storage diseases
A genetic study of 75 patients with hypertrophic cardiomyopathy found that 3 out of 35 patients with negative sarcomere protein mutations had genetical defects in lysosomeassociated membrane protein 2 (LAMP2) responsible for the X-linked disorder Danon's disease/Wolff-Parkinson-White in 2 of the 3, and in AMP-activated protein kinase gamma 2 (PRKAG2) in the remaining, causing Wolff-Parkinson-White/hypertrophic cardiomyopathy (Arad et al., 2005). Both conditions produce glycogen storage and might wrongly be considered as sarcomeric hypertrophic cardiomyopathies. The presence of preexcitation should point to the correct diagnosis. Type IIIa and IV glycogen storage diseases are very rare conditions caused by deficiencies in debrancher and branching enzymes respectively. These patients have muscular hypotonia with elevated creatine kinase and heart and liver involvement. There is heterogenous severity of the disease and the hypertrophic cardiomyopathy is concentric. The inheritance is autosomal recessive (Kishnani et al., 2010). (Fig. 21)

Fabry's disease
Fabry's disease, an X-linked disorder characterized by intracellular accumulation of glycosphingolipids caused by deficiency of the lysosomal enzyme alpha-galactoside A (GLA) may result in late onset hypertrophic cardiomyopathy, therefore it is rare in children.
The reported prevalences in adult males and females with hypertrophic cardiomyopathy are 7.5 and 12% respectively (Chimenti et al., 2004;Sachdev et al., 2002). Enzyme replacement therapy for these patients is available (Eng et al., 2001).

Neuromuscular disorders
Friedreich's ataxia is an autosomic recessive hereditary disorder with spinocerebellar degeneration and frequently associated with hypertrophic cardiomyopathy (Gottdiener et al., 1982). A mutation of the frataxin gene (FXN) alters the energy production through mitochondrial iron dysmetabolism resulting in mitochondrial damage producing muscle fiber fibrosis (Michael et al., 2006). The cardiomyopathy may precede the neurological manifestations (Alday & Moreyra, 1984).

Association with congenital heart disease
Not infrequently, hypertrophic cardiomyopathy and congenital heart disease are associated in children (Somerville & Becu, 1978). In most circumstances the defects are not severe. Ventricular and atrial septal defects and pulmonary valve stenosis have been reported, the last two mainly in patients with Noonan's and LEOPARD syndromes (Bruno et al., 2002;Tikanoja et al., 1999). However, associations with severe conditions like tetralogy of Fallot and atrioventricular septal defect have also been found (Alday et al., 1985;Eidem et al., 2000). (Fig. 22)

Association with left ventricular noncompaction
Left ventricular noncompaction belongs to the category of unclassified cardiomyopathies . It is characterized by the presence of prominent myocardial trabeculations and sinusoid tracts mainly in the left ventricle. (Fig. 23

Treatment
The treatment of hypertrophic cardiomyopathy aims to improve the quality of life alleviating symptoms and to stratify the risk for sudden death to prevent it from happening. Several algorrhythms have been proposed, a slightly modified one is shown in Fig. 24 (Berger et al., 2009). These authors emphasize the existing difficulties to implement prospective controlled randomized trials to define the benefits of different treatment options for this population, therefore most current therapies are empirical or the result of consensus. In older children intensive physical exercise is contraindicated. The disease presenting early has a severe prognosis this being the reason for indicating medical treatment even in asymptomatic children (Bruno et al., 2002). Patients who are symptomatic should receive pharmacological treatment with adrenergic beta blockers which do not decrease the basal outflow gradient but are able to prevent its accentuation in situations of exacerbated inotropism of the heart. Beta blockers also have anti-ischemic properties which increase ventricular filling by decreasing the heart rate. In these patients, calcium channel blockers like verapamil can be an alternative to beta blockers. It is not recommended to use them together. In patients with severe gradients and pulmonary hypertension are not advised because of the danger of precipitating acute pulmonary edema. If there is no improvement, disopyramide, which is an antiarrhythmic drug with negative inotropic effects, is able to decrease basal gradients. The combination of disopyramide and beta blockers has been used succesfully in adults but there is no reported experience in children (Sherrid et al., (2005). For very symptomatic smaller children, in spite of full medical treatment, permanent DDD pacing with short atrioventricular interval to favor the consistent capture of the right ventricle has been used to lower the left ventricular outflow tract obstruction by changing the pattern of left ventricular activation (Alday et al., 1998& Fananapazir et al., 1992. DDD pacing is a reasonable alternative to surgery in symptomatic children despite pharmacological treatment if they are still too young for surgery, taking into account that the approach to an extended septal myectomy is just the aortic valve with a small annulus at this age. A very recent study has also shown progressive relief of symptoms and gradient reduction at long term follow-up (Galve et al., 2010). However, as with other types of treatment, DDD pacing does not protect against the possibility of sudden arrhythmic death (Bruno et al., 2002). The gold standard for the treatment of hypertrophic obstructive cardiomyopathy is still the surgical septal myomectomy (B.J. Maron et al., 2003a;Stone et al., 1993). In experienced centers the mortality is very low and the abolition of the gradient is instantaneous and persistent. The remaining obstruction is usually negligible. These excellent hemodynamic results are associated with improvement of symptoms. The results have been followed for many years and the need for repeat procedures is rare. It should be remembered that the child has to be old enough to permit the transaortic approach to the septum (Berger et al., 2009

Prevention
Risk stratification of sudden death in infants and children differs from what is done in adults. In children, cardiac death occurs infrequently and non sudden cardiac death is as common as sudden arrhythmic death.  (Decker et al., 2009). Sudden cardiac death due to hypertrophic cardiomyopathy occurs mostly in adolescence and early adulthood and very infrequently before 10 years of age. These cases are due to ventricular tachycardia or ventricular fibrillation. In fact, hypertrophic cardiomyopathy is the most common cause of sudden death in the young including athletes (J. Seidman & C. Seidman, 2001). This is the reason why the diagnosis of hypertrophic cardiomyopathy at this age is a strong indication to discontinue the practice of competitive sports. At this time it seems that to establish a prognosis by the knowledge of the specific disease causing mutation is not reasonable for the individual patient. Implantable cardioverter defibrillators are effective to prevent arrhythmic sudden death but in infants and children are indicated mainly in secondary prevention (B.J. Maron, et al., 2000b;. The cardioverter defibrillator implantation is plagued with complications in children, this being the reason for the reluctance of its use in primary prevention (Berul et al., 2008). In a nonrandomized controlled trial amiodarone was at one time reported to improve survival in hypertrophic cardiomyopathy associated with ventricular tachycardia (McKenna et al., 1985). However, the frequent toxic effects of amiodarone might counteract its benefits (Berger et al., 2009). It then could be concluded that the properly functioning cardioverter defibrillator is nowadays the only effective treatment for the prevention of sudden arrhythmic death (B.J. Maron, et al., 2000b).

Screening strategies
It is well known that hypertrophic cardiomyopathy is a genetic disease of the sarcomeric proteins with great heterogeneity of genetic basis and fenotypic expression which does not only involve these structures but also include abnormalities of the connective tissue, mitral valve, and intramural coronary arteries. The genetic defect may be influenced by modifiers genes and unknown enviromental factors. The strategy for clinical screening for hypertrophic cardiomyopathy with 12 lead electrocardiogram and echocardiogram in non affected family members including < 12 year-old children, is optional, unless there is history of early death due to hypertrophic cardiomyopathy or other serious complications in the family, or is an athlete in training, or evidence of incipient left ventricular hypertrophy, or onset of suspicious symptoms. In family members 12 to 18 years of age, clinical follow-up should be performed every 12 to 18 months and from then on every 5 years. The period of screening should be extended to adulthood since we now know that certain mutant genes can provoke a disease of rather late onset (B.J. Maron et al., 2004).

Conclusion
Great strides have been made since the rediscovery of hypertrophic cardiomyopathy in the late 50's last century. Important advances in the understanding of the genetics and physiopathology of the disease have occurred as well as development of superb imaging technologies. Treatment is tailored according to the phenotype and stage of the disease. The very important differences between adult and childhood hypertrophic cardiomyopathy have been underlined in this chapter hoping that will help physicians in decision making when dealing with these patients.

Aknowledgement
We thank Professor Ricardo Pignatelli from Texas Children's Hospital for providing us with excellent images from his personal archives and helpful advice. We also thank Mr. Alfredo Benito from Photographic Resources for helping us with the artwork, and Dr. Ana Grassani for her assistance in the preparation of the manuscript. Finally, we thank our patients for trusting us for many years.