**Acknowledgements**

*Sudden Cardiac Death*

expanded drastically, resulting in revolutionary understanding of the disease. The most important described channelopathies up to date are long QT syndromes (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), early repolarization syndrome (ERS) and idiopathic VF. New disease entities are expected to be discovered in the near future. LQTS is an inherited genetically heterogeneous group of arrhythmias characterized by a prolonged QTc interval in the 12-lead ECGs (with QTc values >470 ms for males and >480 ms for females, representing approximate 99th percentile values). LQTSs as a whole occurs in 1:2500 of the general population. At least 17 genes were identified contributing to LQTSs with mutations positive in about half of the affected individuals. The incidence of LQTSs in decreasing frequency illustrates LQT1 as the commonest (35%) followed by LQT2 (30%) and then LQT3 (10%). The least frequent but most lethal and more difficult to manage is LQT3. Other rare types of LQTSs account for less than 1%. It seems that the normal range of QTc interval is critical for normal AP and normal heart rhythm. Prolongation or shortening of QTc interval is arrhythmogenic. Short QT syndrome with QTc < 350 ms (reported in 1:3400) is etiologically proven cause of malignant VT and VF. Brugada syndrome diagnosed as coved ST-segment elevation in anterior precordial leads occurs in approximately 0.02% up to 0.20% in general population. It overlaps with some of the genetic and clinical features of LQT3. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is relatively a rarely inherited arrhythmogenic disorder (1;10,000) characterized by polymorphic VT induced by physical or emotional stress without any detectable morphological abnormalities in the heart. The most important mutations causing CPVT are in genes encoding cardiac ryanodine type 2 receptor (RYR2) [autosomal dominant] and calsequestrin 2 (CASQ2) [autosomal recessive]. It is considered as highly malignant heart rhythm if neglected. ERS is characterized by elevation of the QRS-ST junction (J point) and QRS notching or slurring (J wave) in multiple leads, especially the inferior and/or left precordial leads. It seems to be more frequent than ever thought with ranges from approximately 6–13% in the general population. Approaching channelopathies in its broad spectrum is an excellent example of the demand of system biology approach in medicine. Channelopathies involving the heart may overlap with manifestations in the nervous system, gastrointestinal system, hearing, infant death syndrome and others. Fatal ventricular arrhythmias are due primarily to abnormal formation or mutations of trans-membrane pores or its regulatory subunits. Aberrancy of cardiac action potential (AP) formation can be interpreted through three main mechanisms: reentry, triggered activity or automaticity. All the different mechanisms described will end up with anomalous action potential. Spatial as well as temporal electrophysiological heterogeneity are important basic electrophysiological derangements that underline cardiac action potential anomalies. Heterogeneity of AP in time and location between myocardium and epicardium are critical predisposing factors to the fatal cardiac rhythm. In comparison to Brugada syndrome, the genetic mutations in LQTS result in tendency for electrical disturbance affecting depolarization rather than repolarization. Surge of catecholamines due to stress or exercise is the substrate fuel of bidirectional VT leading to syncope or SCD in CPVT. RYR2 mutations have also been suggested to be associated with dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. ER pattern is thought to be polygenic with an important contribution of epigenetic and environmental factors. Advances in our knowledge and understanding of disease epidemiology and the basic electrophysiological derangements of channelopathies are intelligent directions that should guide all diagnostic and

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therapeutic approaches.

To the spirit of the later crown prince of Saudi Arabia HRH Sultan Bin Abdulaziz Al Saud, who made my dreams in establishing the prestigious Prince Sultan Cardiac Center reality and from which this science and others are introduced to the world.
