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
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
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.
Functional Consequences of Mutations: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: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 INa.
(mexiletine or lidocaine?).
Functional Consequences of Mutations: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: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:
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
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
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
D. BRUGADA syndromeD. BRUGADA syndrome
E. Congenital short QT syndromeE. Congenital short QT syndrome
C. Polymorphic VT with normal QTC. 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.
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.
Basic Electrophysiology :Basic Electrophysiology :
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).
Basic Electrophysiology :Basic Electrophysiology :
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
D. BRUGADA syndromeD. BRUGADA syndrome
E. Congenital short QT syndromeE. Congenital short QT syndrome
C. Polymorphic VT with normal QTC. 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 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
I. FamilialI. Familial
Identified CausesIdentified Causes
II. Commotio CordisII. Commotio Cordis
III. Idiopathic VFIII. 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. FamilialI. Familial
Identified CausesIdentified Causes
II. Commotio CordisII. Commotio Cordis
III. Idiopathic VFIII. 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 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.