Brugada syndrome

First described in 1992, Brugada syndrome is characterised by an electrocardiogram pattern consisting of coved-type ST-segment elevation in atypical right-bundle branch block in leads V1 to V3, and an increased risk for sudden cardiac death resulting from episodes of polymorphic ventricular tachyarrhythmias.Reference Brugada and Brugada ⁷ Approximately 20–30% of patients with Brugada syndrome have a mutation in the SCN5A gene.Reference Antzelevitch, Brugada and Borggrefe ⁸ The SCN5A gene codifies for alpha subunit of the cardiac sodium channel; it is responsible for the phase 0 of the cardiac action potential, and therefore a key player in the cardiac electrical activity. Mutations in SCN5A result in “loss of function” of the sodium channel. Additionally, there are several mutations described in other 12 more genes – GPD1L, MOG1, SCN1B, SCN3B, CACNA1C, CACNA2D1, CACNB2, HCN4, KCNE3, KCNJ8, KCND3, and KCND5 – although all these genes together have a frequency less than 5%.

The prevalence of Brugada syndrome is between 4% and 12% of all sudden cardiac death causes. The penetrance and expressivity of the disorder are highly variable; Brugada syndrome is generally considered a disorder involving young male adults, with an arrhythmogenic symptom first occurring at the age of 40 years, and sudden death typically occurring during sleep.Reference Vatta, Dumaine and Varghese ⁹ The electrocardiogram pattern can be present at baseline or it may be intermittent. It can be unmasked during a drug challenge with a sodium channel blocker – ajmaline or flecainide in children. The description of acute inducers of the electrocardiogram pattern is of paramount importance, as some individuals may be at risk during anaesthesia, febrile episode, or when they take some oral medications – antidepressants or antiarrhythmics – (www.brugada-drugs.org).Reference Postema, Wolpert and Amin ¹⁰ After surviving a cardiac arrest or the occurrence of syncope, the only treatment having any proven effect on the prevention of sudden death is the implantable cardioverter-defibrillator.Reference Zipes, Camm and Borggrefe ¹¹ Although the Brugada syndrome was described over 15 years ago, little is known about the clinical presentation and prognosis of this disease in children and young adults. The Brugada syndrome can manifest in early childhood and has been diagnosed in infants as young as 2 days old.Reference Antzelevitch, Brugada and Borggrefe ⁸ We know that symptomatic children with spontaneous Brugada electrocardiogram pattern are at high risk, particularly during a febrile illness. Implantable cardioverter-defibrillator implantation in symptomatic children is not free from controversy. The decision to implant a child is not an easy task as this is a life-long therapy, not free from complications, and a cumulative life-long risk for complications – as implantable cardioverter-defibrillator replacements. There are limited data proving the benefit of other preventive therapies such as hydroquinidine, but this has been a good alternative to implantable cardioverter-defibrillator implantation in mid-term follow-up. On the other hand, asymptomatic children diagnosed during family screening seem to have a good prognosis.Reference Probst, Denjoy and Meregalli ¹²

The role of exercise in children and young adults with Brugada syndrome has not been analysed, but considering exercise as an activity that increases body temperature it may be a trigger for cardiac events (Table 5). Even though sudden death in this syndrome is uncommon during exercise, the 2005 36th Bethesda Conference on Eligibility Recommendations for Competitive Athletes with Cardiovascular Abnormalities recommends that people with Brugada syndrome should avoid high-intensity exercise.Reference Zipes, Ackerman and Estes ¹³

Long QT syndrome

Long QT syndrome is a clinically and genetically heterogeneous cardiac channelopathy with a prevalence of 1 in 2500 individuals.Reference Schwartz, Stramba-Badiale and Crotti ¹⁴ It is characterised by prolongation of the QT interval (QTcorrected – QTc – major 460 milliseconds for woman and major 450 milliseconds for men) in otherwise healthy patients with structurally normal heart. The clinical presentation can be variable ranging from asymptomatic to symptomatic individuals with syncope and/or sudden cardiac death due to ventricular tachyarrhythmias (torsade de pointes).Reference Lupoglazoff, Denjoy and Guicheney ¹⁵ The long QT syndrome is one of the leading causes of sudden cardiac death in young people. It can be congenital or acquired, generally in association with drugs and electrolyte imbalance – hypokalaemia, hypocalcaemia, and hypomagnesaemia.Reference Roden ¹⁶ The diagnosis can be made using 12-lead electrocardiogram. However, the penetrance of the disease is not 100%, and therefore individuals and family members at risk with a normal electrocardiogram may be identified through genetic testing. Owing to the ability to identify the individuals at risk through electrocardiogram analysis, massive population screening by electrocardiogram has been performed in certain regions, with success of lowering rates of sudden death among infants and athletes.Reference Corrado, Migliore and Bevilacqua ³

Inheritance of long QT syndrome can follow an autosomal dominant or recessive transmission pattern.Reference Jervell and Lange-Nielsen ¹⁷ To date, more than 700 mutations and splice-site-altering mutations have been identified in several long QT syndrome-susceptibility or long QT syndrome overlap-susceptibility genes (http://www.fsm.it/cardmoc).Reference Kapplinger, Tester and Salisbury ¹⁸ Approximately, 75% of clinically definite long QT syndrome are caused by mutations in three genes: KCNQ1 (long QT syndrome 1), KCNH2 (long QT syndrome 2), and SCN5A (long QT syndrome 3). The remaining 25% have been identified in a variety of ion channels or channel-interacting proteins – SCN4B, CAV3, SNTA1, KCNE1, KCNE2, KCNJ2, KCNJ5, AKAP9, CACNA1C, RYR2, and ANK2.Reference Tfelt-Hansen, Winkel and Grunnet ² The most common form, long QT syndrome type 1, caused by mutations in KCNQ1 is responsible for 40–50% of the cases of prolonged QT interval. Mutations in the long QT syndrome give rise especially to a gain of function in the sodium current – inappropriate prolonged entry of sodium into the myocyte, by mutations in SCN5A or associated proteins, or to a loss of function in the potassium repolarisation currents. Both will result in the prolongation of the cardiac action potential, which will translate in a prolongation of the QT interval in the electrocardiogram.Reference Roden ¹⁶ The clinical course and risk for life-threatening events for adolescents with long QT syndrome have been vastly reported by the international long QT registry. In few terms, a QTc of at least 500 milliseconds in adolescents is considered critical, with a hazard ratio of 2.3 for life-threatening events compared with a QTc less than 500 milliseconds. A history of syncope within the prior 2 years had an adjusted hazard ratio of 11.7–18.1 for events compared with those without syncope.

A practical approach for risk stratification in long QT syndrome has been suggested by Goldenberg et al:Reference Goldenberg, Moss and Peterson ¹⁹

• - Very high risk (secondary prevention):

  • ○ Post cardiopulmonary resuscitation

  • ○ Spontaneous torsade de pointes

• - High risk (primary prevention):

  • ○ QTc >500ms

  • ○ Prior syncope

• - Low risk:

  • ○ QTc <500ms and no prior syncope

Beta-blockers are the standard treatment for the prevention of syncope and sudden death, and should be prescribed for all symptomatic patients.Reference Lupoglazoff, Denjoy and Guicheney ¹⁵ The efficacy of beta-blockers in the prevention of sudden death probably varies according to the genotype – long QT syndrome 1 and long QT syndrome 2.

Depending on the type of long QT syndrome, exercise restrictions exist (Table 5). Long QT syndrome type 3 appears to have a somewhat lower risk during exercise compared with the other types; children with long QT syndrome type 1 may be at particular risk during swimming or diving, but any exercise can be a trigger for malignant arrhythmias.

Short QT syndrome

Short QT syndrome is a new clinical syndrome described in 2000.Reference Gussak, Brugada and Brugada ²⁰ It is associated with a shortened QT interval – QTc minor or equal to 330 millisecondsReference Templin, Ghadri and Rougier ²¹ – on a 12-lead electrocardiogram, tall and narrow T waves, paroxysmal atrial fibrillation, syncope, and an increased risk for sudden cardiac death due to malignant ventricular arrhythmias.Reference Brugada, Hong and Dumaine ²² The short QT syndrome is probably the most severe form of cardiac channelopathy known to date; cardiac arrest has been the most common initial presentation among patients with short QT syndrome. Syncope and sudden death often occur during periods of rest or sleep but may also appear during exertion. Recently, formal diagnostic criteria have been proposed by Gollob et alReference Gollob, Redpath and Roberts ²³ in order to facilitate diagnostic evaluation in suspected cases of short QT syndrome, although some disagreements about it have already been published.Reference Gussak, Brugada and Brugada ²⁰

Sudden cardiac death has been observed during infancy, suggesting the potential role for short QT syndrome as a pathogenic basis for some cases of sudden infant death syndrome. The short QT syndrome is hereditary.Reference Tfelt-Hansen, Winkel and Grunnet ² To date, gain-of-function mutations in three potassium-channel-encoding genes, hERG (also named KCNH2; short QT syndrome 1), KCNQ1 (short QT syndrome 2), and KCNJ2 (short QT syndrome 3) – which are also associated with long QT syndrome – have been confirmed as the molecular basis of the short QT syndrome.Reference Brugada, Hong and Dumaine ²² Expression studies of these mutations show that the ion flow in the affected channels increases as a result of each of these mutations, which results in accelerated repolarisation and therefore a shortened action potential.Reference Gussak, Brugada and Brugada ²⁰ The association of the Brugada syndrome pattern with a shorter QT interval has been associated with mutations in the gene CACNA1C, which causes a change in the unit α calcium channel L-type, inducing a loss of channel function related to the association with Brugada syndrome and QT interval shorter than normal, with autosomal dominant inheritance pattern. With the same phenotype and pattern of inheritance, mutations in CACNB2B cause a change in the unit-type calcium channels, L, giving the association Brugada syndrome and shortened QT interval.Reference Antzelevitch, Pollevick and Cordeiro ²⁴ Recently, a relation between CACNA2D1 and short QT interval has been published.Reference Templin, Ghadri and Rougier ²¹ However, more studies must be conducted to establish a clear clinical–genetic association.

In the majority of patients, electrophysiological studies show decreased atrial and ventricular refractory periods and ventricular vulnerability to arrhythmia. Implantable cardio-defibrillator implantation is the only treatment available, which has proven efficacy in sudden death prevention.Reference Gaita, Giustetto and Bianchi ²⁵ Quinidine has been shown to be the only medication that can prolong the QT interval. However, the severity of the disease reinforces the need to consider the implantable cardio-defibrillator as the first line of therapy.

Few data are reported concerning exercise practice in short QT syndrome. As adrenergic stress has been linked to the development of life-threatening arrhythmias,Reference Gaita, Giustetto and Bianchi ²⁵ neither competitive sport nor moderate leisure-time activity are allowed until more data are available.

Catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia is a heritable arrhythmia syndrome triggered by adrenergic stimulus and mainly expressed during exertion, extreme stress, or emotion.Reference Tfelt-Hansen, Winkel and Grunnet ² It occurs mainly in children and adolescents and is increasingly recognised as a cause of unexplained sudden cardiac death in young individuals in the absence of any other structural heart disease, predominately in young males.Reference Tester, Kopplin and Will ²⁶ Diagnosing catecholaminergic polymorphic ventricular tachycardia can be difficult especially in young children. When presumptive symptoms are encountered, an exercise electrocardiogram and 24-hour Holter monitoring can be very useful in young, physically active children as catecholaminergic polymorphic ventricular tachycardia cannot be diagnosed by a resting electrocardiogram or other cardiologic studies. Catecholaminergic polymorphic ventricular tachycardia is associated with a completely normal resting electrocardiogram – perhaps bradycardia and U waves – and is electrocardiographically suspected by significant ventricular ectopy following either exercise or catecholamine stress testing.Reference Celiker, Erdogan and Karagoz ²⁷

Catecholaminergic polymorphic ventricular tachycardia type 1 is an autosomal dominant disease found in 60% of patients, and most of the mutations are found in the cardiac ryanodine receptor RYR2,Reference Priori, Napolitano and Memmi ²⁸ which is the major regulator of calcium release from the sarcoplasmic reticulum during the plateau phase of the action potential.Reference Denjoy, Postma and Lupoglazoff ²⁹ Mutations in RYR2 gene cause uncontrolled calcium release during catecholamine stimulation. To date, more than 70 mutations have been identified. The other form of the disease, catecholaminergic polymorphic ventricular tachycardia type 2, is a rare autosomal recessive form, caused by homozygous mutations in CASQ2-encoded calsequestrin, which is the major calcium-binding protein within the lumen of the sarcoplasmic reticulum. Catecholaminergic polymorphic ventricular tachycardia type 2 is associated with more severe symptoms and earlier disease onset.Reference Wilde and Bezzina ³⁰ Similarly, some patients diagnosed with catecholaminergic polymorphic ventricular tachycardia type 3 on the basis of the presence of bidirectional ventricular tachycardia on exercise have been identified as possessing KCNJ2 mutations, which are associated with the rarely lethal Andersen–Tawil syndrome or long QT syndrome type 7.Reference Tester, Arya and Will ³¹ The misdiagnosis of Andersen–Tawil syndrome as the potentially lethal disorder catecholaminergic polymorphic ventricular tachycardia may lead to a more aggressive prophylactic therapy than necessary. Genetic testing may provide a clear differential diagnosis between atypical long QT syndrome type 1 and catecholaminergic polymorphic ventricular tachycardia and between catecholaminergic polymorphic ventricular tachycardia and Andersen–Tawil syndrome.Reference Tester and Ackerman ³²

In the absence of treatment, the mortality rate in catecholaminergic polymorphic ventricular tachycardia is very high, reaching 30–50% by the age of 20–30 years.Reference Denjoy, Postma and Lupoglazoff ²⁹ The earlier the episodes appear, the poorer the prognosis, and there is a correlation between the age at which the first syncope occurs and the severity of the disease. The first line of therapy in patients with catecholaminergic polymorphic ventricular tachycardia is beta-blockers, which have significantly reduced syncope and sudden death, with a study suggesting the addition of calcium channel blockers to improve protection. Therapeutic guidelines are based on limited data; however, implantable cardio-defibrillators are indicated for patients with aborted sudden cardiac death or catecholaminergic polymorphic ventricular tachycardia during exercise and in adolescents with incompletely controlled catecholaminergic polymorphic ventricular tachycardia despite a high dose of medications. Considering that the first symptom may be sudden death, it is recommended to treat all genetically identified subjects and those patients who are asymptomatic but have ventricular arrhythmia during exercise. Sport is contraindicated, including those patients treated with beta-blockers.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is one of the most common genetic cardiovascular disorders, affecting 1 in 500 people and is defined by the presence of unexplained left ventricular hypertrophy. Clinically, hypertrophic cardiomyopathy is a disease of variable penetrance and expressivity.Reference Bos, Ommen and Ackerman ³⁴ Hypertrophic cardiomyopathy is the most common cause of premature sudden cardiac death in the young, especially young athletes. Hypertrophic cardiomyopathy is a disease of remarkable genetic heterogeneity (Table 2). Since the discovery of mutations in MYH7 gene-encoded beta myosin heavy chain as a pathogenetic basis for hypertrophic cardiomyopathy, multiple mutations scattered over at least 24 genes that encode essential sarcomeric, calcium-handling, and metabolic regulatory proteins have been identified.Reference Tester and Ackerman ³⁵ The most common genetic forms of hypertrophic cardiomyopathy are related to mutations in genes that encode proteins of the thick and thin myofilaments of the cardiac sarcomere: β-myosin heavy chain (MYH7), regulatory myosin light chain (MYL2), essential myosin light chain (MYL3), myosin-binding protein C (MYBPC3), cardiac troponin T (TNNT2), α-tropomyosin (TPM1), cardiac troponin I (TNNI3), cardiac troponin C (TNNC1), and actin (ACTC).Reference Bos, Ommen and Ackerman ³⁴

Table 2 Hypertrophic cardiomyopathy.

AMP = adenosine monophosphate

Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy patients remains at the forefront of clinical research. Owing to the phenotypic heterogeneity of hypertrophic cardiomyopathy, it is important to find predictors and mechanisms that can explain sudden cardiac death, particularly in relation to exercise.Reference Maron ³⁶ Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise. Genetic testing identifies large numbers of carriers of mutations that cause hypertrophic cardiomyopathy; these carriers often have no or few symptoms. However, recent genotype–phenotype studies described that double (or compound) sarcomere mutations may confer an adverse disease progression and high risk of sudden death. Left ventricle wall thickness z-score major to 6 and an abnormal blood pressure response to exercise are considered clinical factors for sudden death in children.Reference Decker, Rossano and Smith ³⁷ Thus, recent data described that systolic blood pressure does not change during exercise in one-third of the patients.Reference Moak, Leifer and Tripodi ³⁸ It may be due to exaggerated vasodilatory responsesReference Lim, Morris-Thurgood and Frenneaux ³⁹ and to abnormal reflex responses in venous capacitance,Reference Thomson, Morris-Thurgood and Atherton ⁴⁰ increasing left ventricular outflow tract obstruction, myocardial ischaemia, or abnormal diastolic relaxation.Reference Moak, Leifer and Tripodi ³⁸

Differential diagnosis between hypertrophic cardiomyopathy and the so-called “athlete's heart” is not easy, but electrocardiogram, echocardiography, and genetic analysis are useful tools for solving the dilemma, and, of course, detraining during weeks can resolve the problem. Secondary prevention of sudden death in patients successfully resuscitated from cardiac arrest and/or sustained ventricular tachycardia warrants treatment with an implantable cardio-defibrillator.Reference Santini, Russo and Botto ⁴¹ Primary prevention of sudden death in patients considered to be at high risk should aim at the prevention and/or management of ventricular tachyarrhythmias with antiarrhythmic drugs (like amiodarone) and/or implantable cardio-defibrillator implantation, respectively. However, although antiarrhythmic medications had been considered protective against life-threatening events in hypertrophic cardiomyopathy patients, a high rate of sudden cardiac death in patients has recently been described.Reference Melacini, Maron and Bobbo ⁴² Therefore, implantable cardio-defibrillator implantation is the most tenable option for the highest-risk patients. Athletes with a diagnosis of hypertrophic cardiomyopathy should be excluded from most competitive sport, with the possible exception only of those with low intensity in individual cases based on the results of expert cardiovascular evaluation.Reference Pelliccia, Corrado and Bjornstad ⁴³ Competitive exercise is an absolute contraindication for children with hypertrophic cardiomyopathy. Leisure activity, however, is possible if cardiac function allows it.

Dilated cardiomyopathy

Dilated cardiomyopathy is characterised by left ventricular dilatation and left ventricular systolic dysfunction. Right ventricular dilatation and dysfunction may also be present but are not necessary for the diagnosis. Children who present signs of dilated cardiomyopathy with severe systolic dysfunction (less than 30%) have a 5-year mortality index between 40 and 80%, but the incidence of sudden cardiac death in children with dilated cardiomyopathy does not exceed 3%.Reference Pahl, Sleeper and Canter ⁴⁴ There are many factors that can trigger dilated cardiomyopathy, making it a highly heterogeneous entity. Characteristic arrhythmias are seen in both familial and acquired forms: atrioventricular and intraventricular conduction defects, ventricular arrhythmias and atrial fibrillation. In general, a progressive decline in ventricular function occurs in these patients and they die of either cardiac failure or arrhythmic events. This disorder develops at any age, in either sex, and in people of any ethnic origin.Reference Towbin, Lowe and Colan ⁴⁵ In adults, dilated cardiomyopathy arises more commonly in men than in women, with a prevalence of 1 in 2500 individuals, and with an incidence of 7 per 100,000 per year – but it could be underdiagnosed. In children, the yearly incidence is 0.57 cases per 100,000 per year overall, but is higher in boys than in girls (0.66 versus 0.47 cases per 100,000, p-value minor 0.006), in black people than in white people (0.98 versus 0.46 cases per 100,000, p-value minor 0.001), and in babies younger than 1 year than in children (4.40 versus 0.34 cases per 100,000, p-value minor 0.001). Approximately two-thirds of children are thought to have idiopathic disease.Reference Towbin, Lowe and Colan ⁴⁵ Thus, there are no established criteria for the use of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death in children with dilated cardiomyopathy.Reference Pahl, Sleeper and Canter ⁴⁴

The clinical usefulness of genetic analysis in dilated cardiomyopathy is limited.Reference Charron, Arad and Arbustini ⁴⁶ Even so, systematic studies of relatives of patients with dilated cardiomyopathy indicate that at least 35% of the cases are hereditary.Reference Jefferies and Towbin ⁴⁷ In 1994, the first locus of dilated cardiomyopathy with atrioventricular block was identified on chromosome 1.Reference Kass, MacRae and Graber ⁴⁸ To date, several mutations have been identified in genes that encode proteins of the cytoskeleton, cell nucleus, and sarcomere. In less than 10% of the cases,Reference Taylor, Fain and Sinagra ⁴⁹ the mutation occurs in the lamin A/C gene (LMNA),Reference Kass, MacRae and Graber ⁴⁸ which encodes a protein that is expressed in almost all cell types and whose function is to contribute to the integrity of the nucleus by providing mechanical support. Other genes, such as MYH7, MYBPC3, TNNI3, TNNC1, TCAP, VCL, CSRP3, PLN, TPM1, ACTC, and TNNT2 can also cause dilated cardiomyopathy. Recently, a comprehensive genetic study described that titin truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases.Reference Herman, Lam and Taylor ⁵⁰ Moreover, a mutation in the SCN5A gene was identified in a large family with dilated cardiomyopathy.Reference McNair, Ku and Taylor ⁵¹ Three patterns of transmission are described in the inherited forms: (a) Autosomal dominant disease, a locus for which has been reported in several genes – ACTIN, DESMIN, LMNA, and SARCOGLYCAN; (b) X-linked disease, associated with mutations in DYSTROPHIN and TAFAZIN. Although mutations in the DYSTROPHIN gene are not a common cause of dilated cardiomyopathy, direct mutations in this gene give rise to Duchenne- or Becker-type muscular dystrophy, which affect both cardiac and skeletal muscle; (c) Mitochondrial diseases typically affect other tissues beside the myocardium. So far, two loci of dilated cardiomyopathy have been reported in association with primary arrhythmias, one not being the cause of the other. These families had autosomal dominant disease (Table 3). Dilated cardiomyopathy is associated with complex remodelling of one or both ventricles, resulting in a change of the ventricle shape and the architecture of the myocardium fibres. In the most severe cases, affected individuals present signs and symptoms of cardiac failure – diaphoresis, breathlessness at rest or with exertion, orthopnoea, exercise intolerance, early-onset fatigue, abdominal pain, and pallor. Cardiac failure symptoms can be exercise induced or persistent at rest. Therapy of dilated cardiomyopathy is mainly directed at treatment of cardiac failure symptoms and prevention of disease progression and related complications, such as end-organ dysfunction and stroke. Diagnosis, severity of disease, and, if possible, cause of the dilated cardiomyopathy should be known so that therapy can be as precise as possible. On the basis of these recommendations, initial assessment should consist of standard serological testing, transthoracic echocardiography, and, in adults, coronary angiography to assess for possible revascularisation when appropriate. In addition, testing for secondary or specific causes that mimic dilated cardiomyopathy is suggested – with clinical suspicion of haemochromatosis, sleep-breathing disorders, human immunodeficiency virus infection, rheumatologic disease, amyloidosis, or pheochromocytoma. Magnetic resonance imaging can also be helpful for identification of structural and functional abnormalities, especially in the assessment of myocardial viability and scar tissue,Reference Dupuis, Tabib and Reix ⁵² although controversy continues about therapy for myocarditis.Reference Maisch, Hufnagel and Kolsch ⁵³ Exercise is therefore limited to physical capacity, taking into account risk of arrhythmias and cardiac output limitations.Reference van Berlo, de Voogt and van der Kooi ⁵⁴

Table 3 Dilated cardiomyopathy.

ATP = adenosine triphosphate; CoA = coenzyme A; RNA = ribonucleic acid

Restrictive cardiomyopathy

Restrictive cardiomyopathy is one of the rarest forms of cardiomyopathies in which the walls are rigid and the heart is restricted from stretching and filling with blood properly.Reference Williams and Hammer ⁵⁵ Patients with restrictive cardiomyopathy may present palpitations, abdominal enlargement, and sudden cardiac death mainly because of cardiac failure. Children with restrictive cardiomyopathy succumbed to sudden cardiac death, usually within 1 year of diagnosis.Reference Denfield and Webber ⁵⁶ Restrictive cardiomyopathy is extremely rare in childhood, but associated with a very poor prognosis.Reference Hayashi, Tsuda and Kurosaki ⁵⁷ The diagnosis is usually based on a physical examination, an electrocardiogram, and an echocardiogram. However, usually restrictive cardiomyopathy has no cause identified. In the past decade, clinical and genetic studies have demonstrated that restrictive cardiomyopathy is part of the spectrum of sarcomeric disease and frequently coexists with hypertrophic cardiomyopathy. It suggests that the disease may be caused by the same genetic abnormalities as in hypertrophic cardiomyopathy.Reference Denfield and Webber ⁵⁶ For example, mutations in the desmin gene have been found in patients with restrictive cardiomyopathy, dilated cardiomyopathy, or hypertrophic cardiomyopathy, with skeletal myopathy. These conditions have now been termed desminopathies or desmin myopathies. Recently, mutations in cardiac troponin I were also identified in restrictive cardiomyopathy.Reference Sen-Chowdhry, Syrris and McKenna ⁵⁸

Families with multiple individuals who have restrictive cardiomyopathy are likely to have a genetically inherited form, termed familial restrictive cardiomyopathy. The frequency of familial restrictive cardiomyopathy is unknown, but when it occurs it is usually associated with atrioventricular block and skeletal myopathy, although some cases without conduction disease or skeletal myopathy have been reported. Restrictive cardiomyopathy can be idiopathic or secondary to a number of rare cardiac and systemic pathologies such as endomyocardial fibrosis, infiltrative and metabolic disorders.Reference Denfield and Webber ⁵⁶ Although the utility of implantable cardio-defibrillator therapy for children with restrictive cardiomyopathy remains uncertain, the extremely low survival rates underscore the need for early consideration of heart transplantation.

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy characterised by right ventricular dysfunction and ventricular arrhythmias. Patients with arrhythmogenic right ventricular cardiomyopathy pathologically demonstrate fibro-fatty replacement of the myocardium of the right ventricle. Electrocardiogram is not always altered, but the presence of epsilon wave and negative T from V1 to V3 can provide a diagnosis. Children likely present similar symptoms. It is important to remark the difficulty in establishing a diagnosis of arrhythmogenic right ventricular cardiomyopathy because of a wide range of phenotypic expressions. In 1994, a Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy diagnosis was proposed,Reference McKenna, Thiene and Nava ⁵⁹ which was modified recently in order to improve diagnosis.Reference Marcus, McKenna and Sherrill ⁶⁰ About half of all arrhythmogenic right ventricular cardiomyopathy cases are familiar and have mainly an autosomal dominant inheritance pattern with variable penetrance and expressivity. To date, 11 susceptibility genes and some additional genetic loci have been identified – PKP2, DSP, DSG2, DSC2, JUP, DES, TGFB3, TP63, TMEM43, TTN, and recently associated LMNA.Reference Tiso, Stephan and Nava ⁶¹ The majority of cases involve causative genes encoding proteins of mechanical cell junctions or the desmosome, prompting the designation of arrhythmogenic right ventricular cardiomyopathy as a disease of the desmosome or a cell–cell junction disorder (Table 4). Mutations in the JUP gene are responsible for rare homozygous cases of Naxos disease and Carvajal syndrome, which have been related in patients with early age. The clinical picture may include (a) a subclinical phase with concealed structural abnormalities, during which the affected individual may present with cardiac arrest/sudden cardiac death as the first and last manifestation of the disease; (b) an overt electrical disorder with palpitations and syncope due to tachyarrhythmias stemming from the right ventricle, often triggered during effort; and (c) right ventricular or biventricular pump failure so severe as to require cardiac transplantation.Reference Thiene, Corrado and Basso ⁶² However, arrhythmogenic right ventricular cardiomyopathy can involve only right ventricle, even both ventricles, and occasionally early and predominant left ventricle.Reference Deyell, Andrade and McManus ⁶³ A wide spectrum of mutations has been related to the disease, mainly in the PKP2 gene. Genotype–phenotype studies described more severity in nonsense mutations, and patients carrying double mutations showed more severe phenotypes compared with single-mutation carriers.Reference Bauce, Nava and Beffagna ⁶⁴ In addition, arrhythmogenic right ventricular cardiomyopathy is not necessarily arrhythmogenic, so in a sense the acronym of arrhythmogenic right ventricular cardiomyopathy is misleading. The unifying feature is fibro-fatty replacement of the ventricles of the heart, and fibro-fatty cardiomyopathy may be a more descriptive designation.Reference Tester and Ackerman ³⁵ Studies have shown that in patients with an autosomal dominant pattern of arrhythmogenic right ventricular cardiomyopathy 10% of deaths occurred before the age of 19 years and 50% before the age of 35 years.Reference Hamilton ⁶⁵

Table 4 Arrhythmogenic right ventricular cardiomyopathy.

Various mechanisms have been suggested to explain the propensity of arrhythmogenic right ventricular cardiomyopathy to precipitate effort-dependent sudden cardiac arrest. Physical exercise may acutely lead to an increase in the RV afterload and an enlargement of the cavity, which in turn may elicit ventricular arrhythmias by stretching of the diseased right ventricle myocardium.Reference Douglas, O'Toole and Hiller ⁶⁶ In Italy, arrhythmogenic right ventricular cardiomyopathy is one of the most common causes of sudden cardiac death in young athletes, and the mortality is reported to be about 15% during a median 10-year follow-up.Reference Pinamonti, Dragos and Pyxaras ⁶⁷ Children before the age of 8 years rarely met arrhythmogenic right ventricular cardiomyopathy Task Force Criteria, and rarely do sudden deaths occur before the age of 12 years. The pathology is common in athletes who die suddenly, and thus athletes with a diagnosis of arrhythmogenic right ventricular cardiomyopathy should be excluded from competitive sport, with the possible exception of those with low intensity and no related incidence of exercise-related symptoms (Table 5).Reference Pelliccia, Corrado and Bjornstad ⁴³

Table 5 Risk sudden cardiac death in recreational sport.

ARVC = arrhythmogenic right ventricular cardiomyopathy; BrS = Brugada syndrome; HCM = hypertrophic cardiomyopathy; LQT = long QT syndrome

Modified from MaronReference Maron ⁷⁹ and Gersh et alReference Gersh, Maron and Bonow ⁸⁴

Anomalous origin of the coronary arteries

Several congenital coronary artery malformations are the second cause of sudden death in young athletes, accounting for 12–20% of sudden cardiac death cases.Reference Maron ⁶⁸ The anomalous origin of the left main coronary artery from the right (anterior) sinus of Valsalva, with the left coronary artery coursing between the aorta and the pulmonary trunk to reach the left atrioventricular groove, is the most common type found at autopsies of patients with sudden death or death due to anatomical coronary artery anomalies.Reference Maron ⁶⁹ During exertion, increased stroke volume causes expansion of both the aorta and the pulmonary trunk, which can lead to further compression of the already slit-like ostial lumen of the anomalous artery. Decreased blood flow and resultant decreased oxygen supply, in combination with increased oxygen demand during exercise, can lead to myocardial ischaemia. This ischaemia can trigger ventricular arrhythmias and subsequent sudden death. Most patients with coronary artery anomalies are asymptomatic, and those who are symptomatic infrequently complain of typical angina, reporting non-specific symptoms such as syncope, dyspnoea on exertion, and palpitations.Reference Zeppilli, dello Russo and Santini ⁷⁰ Both transthoracic and transoesophageal echocardiography are utilised in diagnosis, although highly trained ultrasound technicians using high-quality imaging systems are required for accurate and consistent identification of the origin of the coronary arteries. When in doubt, computerised tomography can definitely show the precise anatomy.Reference Zeppilli, dello Russo and Santini ⁷⁰ Genetic predisposition for these defects has been identified,Reference Frommelt ⁷¹ but diagnosis is made by echocardiographic findings and if some alteration is identified it should be corrected surgically.

After surgery, sport at high-intensity level is not recommended as coronary arteries have been replaced and residual defects may be present.

Marfan syndrome

Marfan syndrome has an increased risk for sudden death due to aortic dissection.Reference Kinoshita, Mimura and Obayashi ⁷² Aortic root dilation and dissection are secondary to pathological changes in the aorta, namely, cystic medial necrosis.Reference Bader, Goldberg and Sahn ⁷³ The disease is an autosomal dominant genetic disease with variable penetrance, with an estimated incidence of 1 in 7000. It induces particular characteristics such as children who are tall and thin, with arachnid fingers, long face, strong myopic defects, cardiac valve prolepses, and other connective tissue anomalies.Reference Kinoshita, Mimura and Obayashi ⁷² More than 100 mutations on the FIBRILLIN-1 gene have been identified as causes of Marfan syndrome. These mutations lead to defective protein fibrillin in the extracellular matrix, resulting in abnormalities of the ocular, cardiovascular, skeletal, pulmonary, and integumentary systems.Reference Kinoshita, Mimura and Obayashi ⁷² The Berlin nosology or the more recent Gent criteria, which consider family history of Marfan syndrome, skeletal and cardiovascular features, as well as other phenotypic expressions, are used to aid in diagnosis. These characteristics may be subtle, and body habitus measurements may be useful. Echocardiography can be used to measure and monitor the degree of aortic root dilation. Non-Marfan cases of familial aortic root aneurysms are also now being recognised and studied.Reference Bader, Goldberg and Sahn ⁷³ Exercise is not recommended when dilatation is present.

Loeys–Dietz syndrome

Loeys–Dietz syndrome is a severe form of extracellular matrix disease, with more premature sudden death also related to aortic root dilation. Phenotypically similar to Marfan syndrome, the Loeys–Dietz syndrome has the particularity of a bifid uvula, among others. It has an autosomal dominant inheritance pattern, related to a mutation in either the TGFBR1 or TGFBR2 genes, transforming growth factor beta-receptor 1 or 2. These genes encode the receptors for a molecule that plays a role in extracellular signalling. A wide variety of mutations have been identified in both genes; however, there is no significant correlation between the specific mutation, the location of the mutation, or the gene that the mutation is in and clinical presentation. There is no way to predict the severity of vascular, skeletal or skin findings that may occur in an offspring. As in Marfan disease, exercise is contraindicated when dilatation is present.