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Molecular genetic studies have established a link between a number of heritable channelopathies, including congenital long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT), and mutations in genes encoding for ion channels or other membrane components, therefore, have become a golden standard for diagnosing these channelopathies. Clinical diagnosis by standard 12-lead electrocardiography (ECG) at baseline misses some patients, who are genetically affected by these channelopathies (so called concealed form). Therefore, there is a strong need to devise clinical tools to improve the sensitivity of clinical tests to establish the diagnosis of these heritable channelopathies. Provocative testing with catecholamines and pharmacologic testing with sodium channel blockers are critical diagnostic tests in the evaluation of these heritable channelopathies and enable to unmask LQTS, BrS, and CPVT in their concealed state.

Sudden Infant Death Syndrome (SIDS) represents the leading cause of postneonatal sudden death in developed countries, the third leading cause of infant mortality overall in the United States, and a source of devastating psychosocial consequences for the families of victims. This chapter (i) describes the cardiac QT hypothesis for SIDS according to which some cases of SIDS might be due to ventricular fibrillation associated with prolonged repolarization, (ii) summarizes the results of an 18-year long prospective study with electrocardiogram (ECG) recordings in over 34,000 infants, (iii) discusses recent findings which provide the molecular and functional evidence linking SIDS to cardiac channelopathies like the congenital long QT syndrome (LQTS), Short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT), (iv) presents the results of a prospective ECG study involving 45,000 infants which provided the first opportunity for a data-driven assessment of the prevalence of LQTS and summarizes the main finding of a cost-effectiveness study which analyzes a screening neonatal ECG program in a large European country, and (v) addresses the implications of 35 plus years of research on LQTS and SIDS. The studies presented here provide the conclusive evidence that genetically mediated arrhythmias represent a significant and non-dismissible cause of SIDS and support the concept of widespread neonatal ECG screening for the identification of a subset of infants at high risk for sudden death that can be prevented as it is the case with most patients affected by LQTS.

Cardiomyopathies are diseases of the myocardium associated with cardiac dysfunction. According to the World Health Organization (WHO) classification, cardiomyopathies are classified either as primary or secondary cardiomyopathies. Based on morphological and functional criteria, heritable cardiomyopathies are classified into four primary categories including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). More recently, left ventricular non-compaction (LVNC) syndrome has been recognized as a separate cardiomyopathy. Secondary cardiomyopathies include for example ischemic and hypertensive cardiomyopathy. This chapter focuses solely on HCM, the most common heritable cardiovascular disease (estimated prevalence 1:500) and the most common cause of sudden cardiac death (SCD) in young adolescents and athletes. This chapter discusses HCM’s clinical and genetic substrate, genetic testing and screening, and has particular focus on its arrhythmogenic features and the role and indication of the implantable cardioverter defibrillator (ICD) and prevention of SCD.