Diagnosing Cardiac Channelopathies Assembling the Pieces of the Diagnostic Puzzle

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Diagnosing Cardiac Channelopathies Assembling
the Pieces of the Diagnostic Puzzle
2
The Hearts Electrical System

• The heart operates on electrical impulses that
  rhythmically stimulate the atria and ventricles
  so blood can be pumped throughout the body.
• These electrical impulses are controlled by pores
  called ion channels.
• Cardiac channelopathies occur when the proteins
  forming these channels do not function properly.

Normal Electrical Stimulation of the Heart
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Cardiac Channelopathies

• Many syndromes have been identified as cardiac
  channelopathies, including
• - Long QT Syndrome (LQTS)- Brugada Syndrome
  (BrS) - Catecholaminergic Polymorphic
  Ventricular Tachycardia (CPVT) - Short QT
  Syndrome - Anderson Tawil Syndrome (ATS) -
  Congenital Sick Sinus Syndrome
• The fundamental mechanisms responsible for these
  cardiac channelopathies, in large part, have been
  explained.
• Genetic and clinical heterogeneity is common
  among these syndromes.1

Reference 1. Tester DJ, Ackerman MJ. Genetic
testing for cardiac channelopathies ten
questions regarding clinical considerations for
heart rhythm allied professionals. Heart Rhythm.
20052675-677.
4
Cardiac Ion Channels

• The heartbeat is dependent upon the proper flow
  of ions across the cardiac cell membranes.1
• The ion channels mediate the flow of potassium
  (K), sodium (Na) and calcium (Ca2) across the
  myocyte cell membrane and the sacroplasmic
  reticulum.1
• Inherited cardiac channelopathies are disorders
  caused by mutations in ion channel genes that
  result in disturbances to normal heart rhythm.1

Adapted from Marbán E. Cardiac channelopathies.
Nature. 2002415213-218.
Reference 1. Marbán E. Cardiac channelopathies.
Nature. 2002415213-218.
5
Cardiac Action Potential
Adapted from Keating MT, Sanguinetti MC.
Molecular and cellular mechanisms of cardiac
arrhythmias. Cell. 2001104569-580.

• Inward sodium (Na) current mediates the rapid
  phase 0 depolarization.1
• Many outward potassium (K) currents are
  responsible for repolarization phases 2 and 3.1
• Gain of function mutations in the sodium channel
  or loss of function mutations in potassium
  channels may result in QT interval prolongation
  and susceptibility to ventricular
  tachyarrhythmias.1
• These arrhythmias result in symptoms including
  syncope, seizures, and sudden cardiac death.

Reference 1. Keating MT, Sanguinetti MC.
Molecular and cellular mechanisms of cardiac
arrhythmias. Cell. 2001104569-580.
6
Common to Many LQTS Subtypes Is Delayed
Repolarization

• Repolarization abnormalities caused by cardiac
  ion channel mutations can cause QT prolongation
  and tachyarrhythmias.1
• Tachyarrhythmias, especially ventricular
  arrhythmia, can cause a loss of blood pressure
  leading to syncope or sudden cardiac death.1

Most Common Genes Associated With LQTS
Adapted from Keating MT, Sanguinetti MC.
Molecular and cellular mechanisms of cardiac
arrhythmias. Cell. 2001104569-580.
Reference 1. Keating MT, Sanguinetti MC.
Molecular and cellular mechanisms of cardiac
arrhythmias. Cell. 2001104569-580.
7
Assembling the Diagnostic Puzzle for LQTS

• Completing the LQTS diagnostic puzzle is
  essential to developing a comprehensive risk
  assessment to guide clinical decision making.

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Increased Awareness of and Improved Testing for
LQTS Are Revealing a Higher Prevalence

• Inherited LQTS is now known to affect 13,000
  people.1
• It is estimated that 2,000-3,000 children and
  young adults die each year in the United States
  due to LQTS.2

References 1. Taggart NW, Haglund CM, Tester DJ,
Ackerman MJ. Diagnostic miscues in congenital
long-QT syndrome. Circulation. 20071152613-2620.
2. Sudden Arrhythmia Death Syndromes (SADS)
Foundation. LQTS brochure. Available at
http//www.sads.org/LQTS.html. Accessed November
30, 2007.
9
Challenges in Diagnosing LQTS

• Electrocardiogram Variability
• 33 of mutation-positive LQTS carriers have a QT
  interval that overlaps normal, that of healthy
  individuals.1
• Several factors may affect the baseline QT
  interval, including2
• - Genetics
• - Age and gender
• - Central nervous system disorders
• - Electrolyte alterations
• - Certain medications

Adapted from Taggart NW, et al. Diagnostic
miscues in congenital long-QT syndrome.
Circulation. 20071152613-2620.Cell.
2001104569-580.
References 1. Taggart NW, Haglund CM, Tester DJ,
Ackerman MJ. Diagnostic miscues in congenital
long-QT syndrome. Circulation. 20071152613-2620.
2. Maron BJ, Moller JH, Seidman CE, et al.
Impact of laboratory molecular diagnosis on
contemporary diagnostic criteria for genetically
transmitted cardiovascular diseases hypertrophic
cardiomyopathy, long-QT syndrome, and marfan
syndrome. Circulation. 199898(14)1460-1471.
10
Challenges in Diagnosing LQTS

• Disease Variability
• In some families, as many as 33 of LQTS mutation
  carriers will never have a symptom.1
• LQTS is comprised of a diverse set of disease
  subtypes that help define a patients risk for
  cardiac event.
• Clinical signs and symptoms do not adequately
  differentiate LQTS subtype.

Reference 1. Priori SG, Napolitano C, Schwartz
PJ. Low penetrance in the long-QT syndrome
clinical impact. Circulation. 199999(4)529-533.
11
LQTS Comprises a Diverse Set of Disease Subtypes

• Both genetic and clinical characteristic are
  important for assessing risk, recommending
  lifestyle modifications and developing a
  comprehensive treatment plan for each LQTS
  subtype.
• Important differences among LQTS subtypes
  include
• Frequency of symptoms1
• Risk of sudden cardiac death1
• Cardiac event triggers2
• Levels of response to beta-blocker therapy3

Most Common Genes Associated With LQTS
References 1. Zareba W, Moss AJ, Schwartz PJ, et
al. Influence of the genotype on the clinical
course of the long-QT syndrome. N Engl J Med.
199833914960-965. 2. Schwartz PJ, Priori SG,
Spazzolini C, et al. Genotype-phenotype
correlation in the long-QT syndrome
gene-specific triggers for life-threatening
arrythmias. Circulation. 200110389-95. 3. Moss
AJ, Zareba W, Hall WJ, et al. Effectiveness and
limitations of beta-blocker therapy in congenital
long-QT syndrome. Circulation. 2000101616-623.
12
Arrhythmogenic Triggers Differ by LQTS Subtype

• Knowing a patients LQTS subtype will help to
  determine appropriate lifestyle modifications,
  decreasing the risk for cardiac events.1

Adapted from Schwartz PJ, et al.
Genotype-phenotype correlation in the long-QT
syndrome gene-specific triggers for
life-threatening arrythmias. Circulation.
200110389-95.
Reference 1. Schwartz PJ, Priori SG, Spazzolini
C, et al. Genotype-phenotype correlation in the
long-QT syndrome gene-specific triggers for
life-threatening arrythmias. Circulation.
200110389-95.
13
Cardiac Event Frequency and Incidence of Death

• LQT1 patients are more likely than either LQT2 or
  LQT3 patients to experience a cardiac event.1
• Although the incidence of cardiac events is lower
  for LQT3 patients, the probability of death per
  cardiac event is increased.1

Adapted from Zareba W et al. Influence of the
genotype on the clinical course of the long-QT
syndrome. N Engl J Med. 199833914960-965.
Reference 1. Zareba W, Moss AJ, Schwartz PJ, et
al. Influence of the genotype on the clinical
course of the long-QT syndrome. N Engl J Med.
199833914960-965.
14
A Comprehensive Risk Assessment Includes Genetic
Testing

• Identifying individual risk factors is key to a
  comprehensive risk assessment and the development
  of a comprehensive treatment plan.

Gene Mutation Location has been proven to be a
risk factor for LQT1 and LQT2 patients.1,2
References 1. Moss AJ, Shimizu W, Wilde AAM.
Clinical aspects of type-1 long-QT syndrome by
location, coding type, and biophysical function
of mutations involving the KCNQ1 gene.
Circulation. 20071152481-2489. 2. Moss AJ,
Zareba W, Kaufman ES, et al. Increased risk of
arrhythmic events in long-QT syndrome with
mutations in the pore region of the human
ether-a-go-go-related gene potassium channel.
Circulation. 2002105794-799.
15
The Role of Genetic Testing in LQTS

• The Role of Genetic Testing in LQTS

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Combining Genetic Testing and ECG Findings
Yields More Definitive Risk Stratification

• A patients risk of a cardiac event is more
  accurately predicted when LQTS subtype is added
  to gender and QTc.1

Adapted from Priori SG, et al. Risk
stratification in the long-QT syndrome. N Engl J
Med. 2003348(19)1866-1874.

• For patients with a QTc lt 500 msec, risk of
  cardiac events differs based on LQTS subtype.

Reference 1. Priori SG, Schwartz PJ, Napolitano
C, et al. Risk stratification in the long-QT
syndrome. N Engl J Med. 2003348(19)1866-1874.
17
Combining Genetic Testing and ECG Findings
Yields More Definitive Risk Stratification

• A patients risk of a cardiac event is more
  accurately predicted when LQTS subtype is added
  to gender and QTc.1

Adapted from Priori SG, et al. Risk
stratification in the long-QT syndrome. N Engl J
Med. 2003348(19)1866-1874.

• For patients with a QTc 500 msec, risk of
  cardiac events differs based on LQTS subtype.

Reference 1. Priori SG, Schwartz PJ, Napolitano
C, et al. Risk stratification in the long-QT
syndrome. N Engl J Med. 2003348(19)1866-1874.
18
Gene Mutation Location Further Defines LQTS Risk
LQT1
LQT2
Adapted from Moss AJ, et al. Clinical aspects of
type-1 long-QT syndrome by location, coding type,
and biophysical function of mutations involving
the KCNQ1 gene. Circulation. 20071152481-2489.
Adapted from Moss AJ, et al. Increased risk of
arrhythmic events in long-QT syndrome with
mutations in the pore region of the human
ether-a-go-go-related gene potassium channel.
Circulation. 2002105794-799.

• For LQT1 and LQT2 patients, there is
  significantly higher risk for cardiac events when
  mutations are located in the transmembrane (pore)
  region.1,2
• The specific location of each mutation and the
  knowledge of its functional effect contribute to
  a comprehensive risk assessment and more tailored
  therapeutic management.

References 1. Moss AJ, Shimizu W, Wilde AAM.
Clinical aspects of type-1 long-QT syndrome by
location, coding type, and biophysical function
of mutations involving the KCNQ1 gene.
Circulation. 20071152481-2489. 2. Moss AJ,
Zareba W, Kaufman ES, et al. Increased risk of
arrhythmic events in long-QT syndrome with
mutations in the pore region of the human
ether-a-go-go-related gene potassium channel.
Circulation. 2002105794-799.
19
Examples of LQT1 and LQT2 Transmembrane Mutations
KCNQ1/KVLQT1
KCNH2/HERG

• Both of these mutations are classified as a
  probable deleterious mutation because they alter
  protein in the transmembrane region.
• Genetic testing is the only method available to
  determine mutation location.

20
Efficacy of Beta-blocker Therapy for LQTS

• LQT1 and LQT2 patients experience a significant
  reduction in cardiac events withbeta-blocker
  therapy however, beta-blocker therapy has been
  shown to be less effective for LQT2 patients.1
• Beta-blocker therapy has not been shown to
  provide reliable protection against cardiac
  events for LQT3 patients.1

Adapted from Moss AJ, et al. Effectiveness and
limitations of beta-blocker therapyin congenital
long-QT syndrome. Circulation. 2000101616-623.
Reference 1. Moss AJ, Zareba W, Hall WJ, et al.
Effectiveness and limitations of beta-blocker
therapy in congenital long-QT syndrome.
Circulation. 2000101616-623.
21
Value of Family Specific Testing

• ACC/AHA/ESC Guidelines (2006) recommends family
  specific testing upon the identification of a
  gene-positive family member.1
• Without family specific genetic testing, it may
  be difficult to definitively diagnose
  asymptomatic family members.
• Family specific testing enables appropriate
  genetic counseling.

Reference 1. Zipes DP, Camm AJ, Borggrefe M, et
al. ACC/AHA/ESC 2006 guidelines for management of
patients with ventricular arrhythmias and the
prevention of sudden cardiac deathexecutive
summary. J Am Coll Cardiol. 200648(5)1065-1102.
22
ACC/AHA/ESC Guidelines (2006) Recommend Genetic
Testing for Suspected Carriers of Long QT
Syndrome

• Executive Summary
• Genetic analysis is very important for
  identifying all mutation carriers within the LQTS
  family Once identified, silent carriers of LQTS
  genetic defects may be treated with beta blockers
  for prophylaxis of life-threatening arrhythmias.
  Furthermore, silent mutation carriers should
  receive genetic counseling to learn about the
  risk of transmitting LQTS to offspring. In
  patients affected by LQTS, genetic analysis is
  useful for risk stratification and for making
  therapeutic decisions.
• ACC/AHA/ESC 2006 guidelines for management of
  patients with ventricular arrhythmias and the
  prevention of sudden cardiac death

23
ACC/AHA/ESC Guidelines (2006) Recommend Genetic
Testing forSuspected Carriers of Long QT Syndrome

• Risk Stratification
• Genetic testing is often useful in probands
  with a clinical diagnosis of LQTS to provide more
  accurate risk stratification and to guide
  therapeutic strategies.
• It has been shown that the interplay between
  genetic defect, QT duration, and gender may
  provide an algorithm for risk stratification.
• Family Testing
• Genetic analysis is very important for
  identifying all mutation carriers within an LQTS
  family.
• ACC/AHA/ESC 2006 guidelines for management of
  patients with ventricular arrhythmias and the
  prevention of sudden cardiac death

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The FAMILION LQTS Test

• The FAMILION LQTS test will identify a mutation
  in 75 of patients with a high index of
  suspicion for LQTS.1
• The genetic basis for the remaining 25 of LQTS
  remains under investigation.

• Once a gene-positive index case is identified,
  other family members can be tested with the
  FAMILION Family Specific test.

Reference 1. Tester DJ, Will ML, Haglund CM,
Ackerman MJ. Compendium of cardiac channel
mutations in 541 consecutive unrelated patients
referred for long QT syndrome genetic testing.
Heart Rhythm. 20052(5)507-517.
25
Diagnosing Cardiac ChannelopathiesAssembling
the Pieces of the Catecholaminergic Ventricular
Polymorphic Tachycardia(CPVT) Diagnostic Puzzle
26
CPVT Is the Most Lethal of the Cardiac
Channelopathies

• CPVT is an inherited arrhythmogenic disorder
  characterized by ventricular ectopy induced by
  exercise or emotional stress.1,2,3
• CPVT is most commonly caused by mutations of the
  cardiac ryanodine receptor gene (RYR2).1
• 1-2 of CPVT is caused by recessive mutations
  of the calsequestrin (CASQ2) gene.4
• If left untreated, CPVT is lethal in 30-50 of
  patients.1,2
• The onset of CPVT symptoms typically occurs in
  childhood and adolescence.

References 1. Mohamed U, Napolitano C, Priori
SG. Molecular and electrophysiological bases of
catecholaminergic polymorphic ventricular
tachycardia. J Cardiovasc Electrophysiol.
200718(7)791-797. 2. Kontula K, Laitinen PJ,
Lehtonen A, Toivonen L, Viitasalo M, Swan H.
Catecholaminergic polymorphic ventricular
tachycardia recent mechanistic insights.
Cardiovasc Res. 200567379-387. 3. Tester DJ,
Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ.
Targeted mutational analysis of the RYR2-encoded
cardiac ryanodine receptor in sudden unexplained
death a molecular autopsy of 49 medical
examiner/coroners cases. Mayo Clin Proc.
2004791380-1384. 4. Gene Reviews Web site.
Napolitano C, Priori SG. Catecholaminergic
polymorphic ventricular tachycardia. Available
at http//www.ncbi.nlm.nih.gov/books/bv.fcgi?inde
xedgoogleridgene.chapter.cvt. Accessed October
9, 2007.
27
If Left Untreated, Approximately 80 of CPVT
Patients Become Symptomatic

• If left untreated, 30 of CPVT patients will
  develop symptoms by age 10, and 80 by age 40.1

Adapted from Napolitano C, Priori SG. Diagnosis
and treatment of catecholaminergic polymorphic
ventricular tachycardia. Heart Rhythm.
20074675-678.
Reference 1. Mohamed U, Napolitano C, Priori SG.
Molecular and electrophysiological bases of
catecholaminergic polymorphic ventricular
tachycardia. J Cardiovasc Electrophysiol.
200718(7)791-797.
28
Challenges in Diagnosing CPVT

• CPVT cannot be diagnosed on the basis of a
  resting ECG.1,2
• Exercise stress testing is an important part of a
  CPVT workup.
• However, in as many as 20 of CPVT patients,
  formal exercise stress testing will not produce
  ventricular ectopy.1
• During exercise stress testing, bidirectional VT
  with a beat-to-beat 180 degree rotation of the
  QRS complex is often observed.1

References 1. Mohamed U, Napolitano C, Priori
SG. Molecular and electrophysiological bases of
catecholaminergic polymorphic ventricular
tachycardia. J Cardiovasc Electrophysiol.
200718(7)791-797. 2. Kontula K, Laitinen PJ,
Lehtonen A, Toivonen L, Viitasalo M, Swan H.
Catecholaminergic polymorphic ventricular
tachycardia recent mechanistic insights.
Cardiovasc Res. 200567379-387.
29
It Is Important to Differentiate Between CPVT
and LQT11

• CPVT is an LQT1 mimicker.2
• As many as 30 of CPVT patients have been
  misdiagnosed as having Long QT with normal
  QTc.1,3
• Differentiating CPVT from LQT1 is important for
• - Developing a comprehensive treatment plan
• - Family specific testing

References 1. Priori SG, Napolitano C, Memmi M,
et al. Clinical and molecular characterization of
patients with catecholaminergic polymorphic
ventricular tachycardia. Circulation.
200210669-74. 2. Choi G, Kopplin LJ, Tester DJ,
et al. Spectrum and frequency of cardiac channel
defects in swimming-triggered arrhythmia
syndromes. Circulation. 20041102119-2124. 3.
Napolitano C, Priori SG. Diagnosis and treatment
of catecholaminergic polymorphic ventricular
tachycardia. Heart Rhythm. 20074675-678.
30
The Addition of Genetic Testing to the Workup Can
Help Differentiate CPVT from LQT1
31
Beta-blockers Do Not Provide Reliable Protection
Against Cardiac Arrhythmias Related to CPVT1

• However, in light of incomplete protection
  afforded by beta-blockers in CPVT, its
  distinction from long-QT is clinically
  relevant.1
• - S. Priori MD, 2002
• Nearly 50 of CPVT patients taking a beta-blocker
  continue experiencing cardiac arrhythmias and may
  require an ICD.1

Reference 1. Priori SG, Napolitano C, Memmi M,
et al. Clinical and molecular characterization of
patients with catecholaminergic polymorphic
ventricular tachycardia. Circulation.
200210669-74.
32
ACC/AHA/ESC Guidelines (2006) Recommend Genetic
Testing for Suspected Carriers of CPVT
Genetic analysis may help identify silent
carriers of catecholaminergic VT-related
mutations once identified, silent carriers may
be treated with beta blockers to reduce the risk
of cardiac events and may receive appropriate
genetic counseling to assess the risk of
transmitting the disease to offspring. ACC/AHA/E
SC 2006 guidelines for management of patients
with ventricular arrhythmias and the prevention
of sudden cardiac death
33
The FAMILION CPVT Test

• The FAMILION CPVT test will identify a mutation
  in up to 55 of patients with a high index of
  suspicion for CPVT.1
• Once an index case has tested positive for a gene
  mutation, other family members can be tested
  using the FAMILION Family Specific test.

Reference 1. Napolitano C, Priori SG. Diagnosis
and treatment of catecholaminergic polymorphic
ventricular tachycardia. Heart Rhythm.
20074675-678.
34
The FAMILION Family of Genetic Tests

• Two technologists independently score all traces
  for variants, and a supervisor reconciles any
  discrepancy.1
• All traces of variants are reviewed and approved
  by an ABMG board certified molecular
  geneticist.1
• For each positive finding of a Class I or II
  variant, a second round of PCR amplification and
  sequencing are completed to confirm the initial
  finding.1
• Identified variants are interpreted with respect
  to a reference population of several hundred
  healthy individuals and a database of hundreds of
  known mutations.

Reference 1. The FAMILION Tests Technical
Specifications, October 2007. ABMG - American
Board of Medical Genetics
35
Many Health Insurance Providers Deem Genetic
Testing Medically Necessary
Medical necessity may be defined differently by
each insurance provider.
36
PGxHealth Offers Reimbursement Services

• PGxHealth will assist each patient by working
  with the insurance provider to pre-authorize
  services and determine benefit information upon
  request.
• PGxHealth will contact the patient with this
  information prior to the initiation of testing.
• PGxHealth will be quoted an estimate of coverage
  from the insurance carrier but cannot guarantee
  reimbursement.
• Following the completion of testing, PGxHealth
  will file the insurance claim with the provider.