Cairo University

 In the truly normal heart SCD, is an uncommon occurrence.  The majority do not actually have "normal" hearts, but our diagnostic tools limit identification of structural or functional derangement.  In the truly normal heart SCD, is an uncommon occurrence.  The majority do not actually have "normal" hearts, but our diagnostic tools limit identification of structural or functional derangement. Myerburg, 1997 Wever et al., 2004

 The most common underlying disorders:  Hypertrophic Cardiomyopathy (36 percent)  An Anomalous Coronary Artery (13 %), and  Myocarditis (7 percent). Epidemiology Maron et al., 2003 “An autopsy series from the USA in (286 competitive athletes under age 35)”

 Electrolyte Abnormalities, such as: Hypokalemia and Hypomagnesemia, Can precipitate SCD in susceptible subjects. Siscovick et al., 1998

I. Familial Identified Causes II. Commotio Cordis III. Idiopathic VF

A.WPW and other forms of SVT Familial Causes of SCD B.The long QT syndrome C.Polymorphic VT with normal QT D.BRUGADA syndrome E.Congenital short QT syndrome

 SVT associated with the WPW syndrome can cause SCD in 2.1%.  AF with a rapid ventricular response: is the most common.  Atrioventricular Nodal Reentrant Tachycardia (AVNRT) or AF with a rapid ventricular response may deteriorate into VF in 2.4 percent.  SVT associated with the WPW syndrome can cause SCD in 2.1%.  AF with a rapid ventricular response: is the most common.  Atrioventricular Nodal Reentrant Tachycardia (AVNRT) or AF with a rapid ventricular response may deteriorate into VF in 2.4 percent. A. WPW and other forms of SVT: Wang et al., 1991

A.WPW and other forms of SVT Familial Causes of SCD B.The long QT syndrome C.Polymorphic VT with normal QT D.BRUGADA syndrome E.Congenital short QT syndrome

 An imbalance in sympathetic cardiac innervation could lead to prolongation of the QT interval and risk of arrhythmia. Mechanistic Model:

The trigger for early afterdepolarizations is Reopening of Cardiac L-type Calcium Channels during the prolonged plateau phase of the cardiac action potential. The beneficial effect of  - adrenergic blockers may be caused by a blunting of the increase in L-type calcium current by sympathetic nerve stimulation. Cellular Model:

The recognition that LQTS is actually a group of ion channel diseases with a similar phenotype has led to the new terminology for mutations: (1) LQT1 on KvLQT1, (2) LQT2 on HERG, (3) LQT3 on SCN5A, and (4) LQT5 on mink. LQTS Genes:

LQT 2 is caused by mutations in the HERG (human ether-a-go-go-related gene), a potassium channel gene responsible for the rapid component of Delayed Rectifier Potassium Current Ikr in ventricular myocytes. Gene Mutations:

1. When mutations in KvLQT1, KCNE1, or HERG are expressed alone or with wild-type alleles they exhibit “Loss of Function”, ie, the total current carried by the defective channel complexes is reduced. Functional Consequences of Mutations:

2.Mutations in the SCN5A channels cause a “Gain of Function”. These mutations produce a persistent late I Na that is not present physiologically and that is due to defective inactivation. In most described mutations, the I Na is increased because of late Reopenings of the Channels. Functional Consequences of Mutations:

3.Most HERG mutations, however, are MISSENSE Mutations that have a dominant- negative effect on HERG function. “lead to the synthesis of HERG subunits that are usually nonfunctional when they are expressed alone”. Functional Consequences of Mutations:

It is generally difficult to develop specific therapies for loss of function (eg, the K + channel defects). By contrast, the gain of abnormal function exhibited by mutant SCN5A gene products raises the possibility that a cure could be accomplished by pharamcological agents that inhibit the gained function, ie, block the late I Na. (mexiletine or lidocaine?). Functional Consequences of Mutations:

A mechanistic understanding of long QT syndrome may enable treatment. Historically, patients with LQT have been treated with  Beta-adrenergic antagonists,  Left Cervical Sympathectomy, or  Implantation of permanent pacing devices and  Automatic defibrillators. Therapeutic Implications:

The putative role of IK s in cardiac physiology suggests an especially favorable effect of beta blockade and the avoidance of vigorous increase in heart rate (ie., competitive sports) in LQT1 and LQT5. These examples demonstrate that Gene-Specific Therapy may be feasible in LQTS. Therapeutic Implications:

Drug-induced LQTS might represent a genetically mediated “forme fruste” of LQTS. Recent studies have identified relatively large numbers of individuals who carry “silent” mutations on LQTS genes.

Genetic testing could be useful, because depending on the gene (and ultimately even the specific mutation), modifications in management may be suggested:  The addition of mexiletine in LQT3 or  Lifestyle modifications such as limitation of strenuous or competitive exercise in LQT1. Genetic Testing for LQTS:

A.WPW and other forms of SVT Familial Causes of SCD B.The long QT syndrome C.Polymorphic VT with normal QT D.BRUGADA syndrome E.Congenital short QT syndrome

 Affected patients typically present with life- threatening VT or VF occurring during emotional or physical stress, (syncope often being the first manifestation of the disease).  Although sporadic cases occur, this is primarily a Familial Disease (also called Catecholaminergic VT).

Occurrence of polymorphic ventricular tachycardia after exercise testing

Some cases are due to mutations in the Cardiac Ryanodine Receptor, (the Cardiac Sarcoplasmic Calcium Release Channel). May account for at least one in every seven cases of sudden unexplained death). Tester et al., 2004

A.WPW and other forms of SVT Familial Causes of SCD B.The long QT syndrome D.BRUGADA syndrome E.Congenital short QT syndrome C.Polymorphic VT with normal QT

Characterized by the electrocardiographic findings of:  (RBBB) and  ST-segment elevation in leads V1 to V3, and  An increased risk of sudden death. Brugada syndrome may represent either a:  Functional abnormality in the electrical activity of the heart i.e (primary electrical disease, channelopathy) or  An early subclinical manifestation of arrhythmogenic right ventricular dysplasia (ARVD).

Variation in the precordial lead ST and T waves in a patient with Brugada syndrome.

Electrophysiological Basis and Genetics : Additional features include: (1) unmasking of the characteristic ECG changes by sodium channel-blocking drugs such as ajmaline, flecainide, and procainamide.

(2) Autosomal dominant pattern of inheritance, but with marked male predominance; and (3) usual presentation in the fourth decade of life despite the presence of the underlying defect(s) at birth. Antzelevitch et al 2003 Electrophysiological Basis and Genetics :

Basic Electrophysiology : Regional Heterogeneities in Action Potential Characteristics between the right and left ventricles, and the epicardium, midmyocardium and endocardium. Antzelevitch et al 2002

The presence of three dominant cell types, epicardial, M, and endo­cardial cells is a basis for the action potential variations. The three cell types display quantitative differences in the density of the various ionic currents that contribute to the generation of the normal action potential. Basic Electrophysiology :

Heterogeneity of action potential characteristic's across ventricu­lar wall: Pemel (A) shows typical action potentials recorded from epicardial and endocardial cells. The epicanlud action potential has a prominent notch durinr; phase I and a "spike and dome" configuration. The NI-cell also has a prominent phase 1 and the longest duration of action potentials across the ventricular wall. Phase 1 is relatively prominent in endocardial cells. Panels (B) and (C) show the membrane currents recorded from each cell type. Epicandial cells have a transient outward potassium current while this current is diminutive in endocardial cells. The slow component of the de­layed rectifier current is diminished in M-cells.25 Reprinted with permission from Blackwell Publishing.

This sets up a voltage gradient between epicardium and endocardium that is evident on the ECG as ST-segment elevation. Current from the endocardium to the epicardium can result in closely coupled extrasystoles and the initiation of ventricular fibrillation. (phase 2 reentry). Basic Electrophysiology :

A.WPW and other forms of SVT Familial Causes of SCD B.The long QT syndrome D.BRUGADA syndrome E.Congenital short QT syndrome C.Polymorphic VT with normal QT

 A Familial Syndrome characterized by an abnormally short QT interval: (Corrected QT interval “QTc” < 0.30 sec) and  Associated with an increased risk of SCD.  All Family members had histories of syncope, palpitations, AF, and, in one case, resuscitated SCD.  On electrophysiologic evaluation, all had short atrial and ventricular refractory periods, and frequently had inducible VF. Gussak et al 2000

A. Schematic representation of the normal action potential and the flux of ions. B. With gain-of-function mutations in any of 3 different potassium channels, the cardiac action potential shortens and the QT interval decreases.

Because shortening of the QT interval is likely due to an increase in the outward current, blocking the current with class III antiarrhythmic drugs (which are known to increase the QT interval) may be a therapeutic approach for treating short QT syndrome. No large randomized trials have been conducted to date on drug therapies for the syndrome. The current evidence is derived from small studies. Pharmacologic Therapy

Electrocardiogram of a patient with short QT syndrome. Observe the tall peaked T waves.

The first line of therapy, especially in people recovered from sudden cardiac death or with a history of syncopal episodes, is the implantation of Cardioverter Defibrillator. Therapeutic Options: Schimpf et al., 2003

I. Familial Identified Causes II. Commotio Cordis III. Idiopathic VF

 Most often occurs in Young Athletes who have been struck in the precordium with a projectile object such as a baseball, hockey puck, or fist.  Mostly during organized or recreational sporting activities, an during routine daily activities.  Usually accidental, although some have resulted in criminal liability Maron et al., 2002

An animal model was developed in which low- energy blows to the chest wall would produce: VF if delivered during repolarization, just before the peak of the T wave, produced VF, Transient Complete Heart Block followed by ST segment elevation if delivered during depolarization, and during the QRS complex. The frequency of VF was related to the hardness of the projectile and impact speed. Link et al., 2003

I. Familial Identified Causes II. Commotio Cordis III. Idiopathic VF

 If the above disorders are excluded and the heart is structurally normal, the diagnosis of idiopathic VF (also called primary electrical disease) is made.  Estimated to account for 5 percent of cases of SCD.  The mean age was 36 years with a  Male-to-female ratio of 2.5:1.  A history of syncope preceded the episode of VF in 25 percent. Viskin & Belhassen, 1990

Relatively localized areas of abnormal myocardium with functional activation delay, while other regions were minimally abnormal or normal (heterogeneous disease). Electrophysiologic Basis Saumarez et al., 2003

Among survivors of SCD due to idiopathic VF, the reported rate of recurrent VF ranges between 22 and 37 percent at two to four years. Prognosis: Marcus 1997

1. Because they have no structural heart disease, these pts have an excellent prognosis for long- term survival if VF is prevented. As a result, such patients are best treated with an ICD. Management Meissner et al., 1993

2. Another possible therapeutic approach is Mapping and Radiofrequency Ablation. Triggering premature beats were elicited from the Purkinje system and less frequently from the right ventricular outflow tract in four. At a mean follow-up of two years after local RF ablation, 24 pts (89 percent) had no recurrence of VF. Haissaguere et al., 2002 Management

1. A direct link between Mitral Valve Prolapse and SCD has not been established unless there is:  Valve redundancy or thickening,  A family history of SCD, or perhaps,  Significant mitral regurgitation,  QT interval prolongation, or  ST-T waves changes

2.AF in patients less than 70 years of age and AF in the absence of ventricular preexcitation or hyperthyroidism is associated with an increase in total mortality, but not SCD. 3.Isolated Ventricular Premature Beats are associated with an increased risk of subsequent SCD only in patients with structural HD or with risk factors for CHD. Viskin & Belhassanm 1990

1.Inducible Ventricular Arrhythmia with a Nonaggressive protocol:  Common in idiopathic VF,  A more aggressive protocol is generally necessary in patients without such a history. An inducible arrhythmia may be important:

2.Repetitive induction of polymorphic VT with the same protocol, particularly when stimulating from different sites, or 3.A change from polymorphic to sustained monomorphic VT suggests that the arrhythmia may be clinically relevant. 4.The identification and treatment of accessory bypass tracts and supraventricular arrhythmias with 1:1 conduction, such as atrial flutter.

5. Substrate Mapping of the epicardium and endocardium may identify areas of scar indicating abnormal substrate and a predisposition to ventricular arrhythmia. Josephson et al., 1980

6. Even in the absence of scar, some patients with idiopathic VF have electrophysiologic abnormalities, including: A. A Purkinje potential (an initial sharp potential, <10 ms in duration, prior to the ventricular electrogram), B. Ventricular areas of slow conduction, C. Regionally delayed repolarization, or D. Dispersion in repolarization. This conduction delay may be exacerbated by an acute rise in vagal activity, possibly leading to random reentry and VF. Haissaguerre et al., 2002 Peeters et al., 1998

The exact mechanism of collapse in an individual patient is often impossible to establish since patients who die suddenly are seldom under close observation. As a result, the mechanism can only be inferred, based upon information obtained after the process has been initiated.

However, there have been many cases in which the initiating event has been witnessed or recorded. This has usually occurred in patients:  Being continually monitored in the coronary care unit or  With a 24-hour ambulatory ECG recording device or  An implantable cardioverter-defibrillator (ICD). Ventricular tachycardia (VT) or ventricular fibrillation (VF) account for the majority of episodes. However, a bradyarrhythmia is responsible for some cases of SCD.