Cairo University. In the truly normal heart SCD, is an uncommon occurrence. The majority do not actually have "normal" hearts, but our diagnostic.

Cairo UniversityCairo 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).

EpidemiologyEpidemiology

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. FamilialI. Familial

Identified CausesIdentified Causes

II. Commotio CordisII. Commotio Cordis

III. Idiopathic VFIII. Idiopathic VF

A. WPW and other forms of SVTA. WPW and other forms of SVT

Familial Causes of SCDFamilial Causes of SCD

B. The long QT syndromeB. The long QT syndrome

C. Polymorphic VT with normal QTC. Polymorphic VT with normal QT

D. BRUGADA syndromeD. BRUGADA syndrome

E. Congenital short QT syndromeE. 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:A. WPW and other forms of SVT:

Wang et al., 1991







An imbalance in sympathetic cardiac

innervation could lead to prolongation of

the QT interval and risk of arrhythmia.

Mechanistic Model: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: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:LQTS Genes:

LQT2 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: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:Functional Consequences of Mutations:

2. Mutations in the SCN5A channels cause a “Gain

of Function”. These mutations produce a

persistent late INa that is not present

physiologically and that is due to defective

inactivation. In most described mutations, the INa is increased

because of late Reopenings of the Channels.


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”.


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 INa.

(mexiletine or lidocaine?).


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:Therapeutic Implications:

The putative role of IKs 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: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:Genetic Testing for LQTS:







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

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







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.

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

Electrophysiological Basis and Genetics :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 :Electrophysiological Basis and Genetics :

Basic Electrophysiology :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 endo cardial 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.


Heterogeneity of action potential characteristic's across ventricu lar 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 de layed 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).








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 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:Therapeutic Options:

Schimpf et al., 2003





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





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 BasisElectrophysiologic 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: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.

ManagementManagement

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

ManagementManagement

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: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., 2002Peeters 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.

Cairo University. In the truly normal heart SCD, is an uncommon occurrence. The majority do not actually have "normal" hearts, but our diagnostic.

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