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The increasing interaction between molecular biology and clinical cardiology has allowed to demonstrate that mutations on the genes encoding cardiac ion channels or regulatory proteins can cause inherited arrhythmogenic disorders predisposing to sudden death in young individuals. These diseases are the long QT syndrome, the Brugada syndrome, the catecholaminergic polymorphic ventricular tachycardia, and the short QT syndrome. Since incomplete penetrance is present, genetic screening is pivotal to perform a correct diagnosis in mutation carriers who do not manifest phenotype, but are still at increased risk of cardiac events if left untreated. All these syndromes show genetic heterogeneity and it is becoming evident that each genetic variant of the disease presents distinguishing clinical characteristics suggesting that genetics may be used for targeting risk stratification and treatment of these diseases. In this chapter, the molecular bases, the clinical features and the current therapeutic approach of these syndromes are presented.

A case of long QT syndrome diagnosed in the early neonatal period is described. A full-term male baby was delivered by cesarean section at 38 weeks of gestation. The indication to cesarean section was sudden marked fetal bradycardia. At birth, he presented the following rhythm disorders: a) an ectopic atrial rhythm with T wave alternans, and b) atrioventricular conduction disorders. Sinus rhythm, with a prolonged QT interval and T wave alternans, was recovered soon after birth, before starting beta-blocker therapy. The family history was negative for the long QT syndrome: sudden unexpected death and/or syncopal episodes and cases of congenital deafness have not been reported. Molecular screening of the five long QT syndrome-related genes did not reveal the presence of any mutation. At 3 years of follow-up, the child is well and he did not present with symptoms or arrhythmias during this period.

Brugada syndrome is an arrhythmogenic disease, characterized by syncope and sudden cardiac death, with a typical electrocardiographic pattern: right bundle branch block and ST segment elevation in the right precordial leads. Only recently, the first gene causing Brugada syndrome has been demonstrated by the identification of mutations in SCN5A, the gene encoding for the cardiac sodium channel, also responsible for the LQT3 subtype of long QT syndrome. Despite the knowledge on Brugada syndrome has dramatically improved in the recent years, the clinical management is still often empirical and limited by the lack of pharmacological therapies. Therefore, the implantable cardioverter-defibrillator (ICD) is the only life-saving option for high-risk patients. However, life-long implant in young individuals may have a major impact on the quality of life and it is not free from complications. Therefore, the identification of a robust risk stratification algorithm is of outmost importance to limit the use of ICD to the higher risk individuals. Programmed electrical stimulation has been proposed but this approach appears to have a low positive predictive value, thus leading to implants in many asymptomatic patients. Recently, we analyzed data from 200 Brugada syndrome patients, one of the largest groups so far reported, and we showed that the best predictor of cardiac events is the presence of a spontaneous abnormal ECG pattern associated with history of syncope. In the present article we will review the clinical characteristic of Brugada syndrome and point out a possible risk stratification scheme.

In clinical cardiology, resort has recently been made to molecular genetics in order to explain some mechanisms that underlie sudden cardiac death in young people with structurally normal hearts. It has become evident that genetic mutations regarding cardiac ion channels may disrupt the delicate balance of currents in the action potential, thus inducing malignant ventricular tachyarrhythmias. The cardiac sodium channel gene, SCN5A, is involved in two of such arrhythmogenic diseases, the Brugada syndrome and one form of the long QT syndrome (LQT3). It is believed that these syndromes result from opposite molecular effects: Brugada syndrome mutations cause a reduced sodium current, while LQT3 mutations are associated with a gain of function. The effects of class I antiarrhythmic drugs have been used to differentiate these diseases. Intravenous flecainide is used as a highly specific test to unmask the electrocardiographic phenotype of the Brugada syndrome. On the other hand, on the basis of experimental and clinical studies, the possibility that the same drugs act as a gene-specific therapy in this disorder by contrasting the effect of mutations in LQT3 has been explored. Recent evidence shows that phenotypic overlap may exist between the Brugada syndrome and LQT3. One large family with a SCN5A mutation and a "mixed" electrocardiographic pattern (prolonged QT interval and ST-segment elevation) has been reported. Moreover, our recent data showed that flecainide challenge may elicit ST-segment elevation in some LQT3 patients. The presence of "intermediate" phenotypes highlights a remarkable heterogeneity suggesting that clinical features may depend upon the single mutation. Only deepened understanding of the genotype-phenotype correlation will allow the definition of the individual patient's risk and the development of guidelines for clinical management.

Background: In the long QT syndrome (LQTS) most life-threatening cardiac events occur in association with physical or emotional stress. However, a minority of patients dies suddenly during sleep; intriguingly, these sleep-related sudden deaths tend to cluster in families. The mechanism(s) underlying this phenomenon and the reason why it occurs in few selected families are unknown. Recently, some of the LQTS genes have been identified leading to three main subgroups (LQT1, LQT2, LQT3) associated respectively with mutations affecting the following ionic currents involved in the control of ventricular repolarization: I(Ks), I(Kr), I(Na). We have recently observed that cardiac events nighttime are rare in LQT1 and frequent in LQT3 patients., Methods: We studied 26 LQTS patients all genotyped (11 LQT1, 9 LQT2, 6 LQT3) and 26 healthy controls matched by age and gender. Using a specific software, 24-hour ambulatory ECG recordings were performed and the QT interval was measured in order to allow comparison between QTc nighttime and daytime., Results: The main finding is that while LQT1 patients show a trend for modest QTc shortening and LQT2 patients a trend for modest lengthening nighttime versus daytime, LQT3 patients show clear lengthening of the QTc nighttime. These changes are not explained by heart rate changes or by the use of beta-blockers., Conclusions: The marked tendency for further QT prolongation nighttime, which clearly increases arrhythmic risk, present among LQT3 patients and absent among LQT1 patients, provides an explanation for the gene-specific higher risk for sudden death during sleep for LQT3 compared to LQT1 patients.