Genetic Testing is a Blessing: Cardiac Channelopathies Batra Pro Debate 12 15 pm.pdfcheerleader, Shauna was both physically fit and the picture of health at the time her death. zShauna

1January 14-15, 2011 SCA Conference

Genetic Testing is a Blessing:Cardiac Channelopathies

Anjan S Batra, M.DDirector of ElectrophysiologyAssociate Professor of PediatricsUniversity of California-Irvine

Common Inherited Diseases that Cause Sudden Arrhythmic Death Syndrome (SADS)

More than 50% of SADS deaths are genetic in nature.1

Reference: 1. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in majority of families. Eur Heart J. 2008;29:1670-1680.


The Family of Genetic Tests for Inherited Cardiac Syndromes

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

Inherited LQTS is now known to affect 1:2,500 people.1

It is estimated that 2,000-3,000 children and young adults die each year in the United States due to LQTS 2each year in the United States due to LQTS.2

References: 1. Crotti L, et al. Congenital long QT syndrome. Orphanet Journal of Rare Diseases. 2008;3:18. 2. Sudden Arrhythmia Death Syndromes (SADS) Foundation. LQTS brochure. Available at: http://www.sads.org. Accessed November 30, 2007.


Challenges in Diagnosing LQTS –ECG Variability

33% f t ti~33% of mutation-positive LQTS patients have a QT interval (≤ 480 msec) that overlaps normal, healthy individuals.2

Adapted from: Taggart NW, et al. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007;115:2613-2620.Cell. 2001;104:569-580.

References: 1. 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. 1998;98:1460-1471. 2. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007;115:2613-2620.

Schwartz ScoreSchwartz score results are frequently inconclusive 1inconclusive.

Probability Pts

High 4

Reference: 1. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-533.

intermediate 2-3

Low 1


THE BENEFITS OF GENETIC TESTING?

Genetic Testing for PreventionFrequency of Cardiac Events

Subjects from the International LQTS Registry & BIOMED LQTS Research Group


Gene Mutation Location Further Defines LQTS RiskLQT1 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. 2007;115:2481-2489.

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. 2002;105:794-799.

For LQT1 and LQT2 patients, there is significantly higher risk for cardiac events when mutations are located in the transmembrane/pore region.1,2

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. 2007;115:2481-2489. 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. 2002;105:794-799.

Examples of LQT1 and LQT2 Transmembrane Mutations

KCNQ1/KvLQT1 KCNH2/HERG

Genetic testing is the only method available to determine mutation location.


Risk for Asymptomatic Parents of Probands Risk of an Initial Cardiac Event for Asymptomatic Parents of Probands Extends Into Adulthood.

Reference: 1. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001;104:557-562.

Adapted from: Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001;104:557-562.

Genetic Testing for TherapyEffectiveness of β-Blocker Treatment

Rate of cardiac events over five years for subjects from the International LQTS Registry

Mohammed et al.J Cardiovasc Electrophysiol. 2007;18(7):791-797.


Genetic Testing for Therapy

TEST ISSUE DIRECTED RESULTS THERAPYLQT 1 Experience events

during exercise. Endangered by exercise.

Avoid competitive sports. Beta blocker therapy advised.

LQT 2 Auditory stimuli trigger events.

Remove alarm clocks etc. from bedroom. Beta blocker therapy advised.

LQT 3 Relatively low risk of exercise. High mortality rates despite beta blocker therapy.

Supervised recreational activity could be considered.ICD therapy advised.

Genetic Testing for PrognosisLQT1 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. 1998;339:14:960-965.

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. 1998;339:14:960-965.


Symptoms in CPVTIf 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. 2007;4:675-678.

Reference: 1. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol. 2007;18:791-797.

Challenges in Diagnosing CPVTCPVT 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 1stress 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. 2007;18:791-797. 2. Kontula K, Laitinen PJ, Lehtonen A, Toivonen L, Viitasalo M, Swan H. Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights. Cardiovasc Res. 2005;67:379-387.


Differentiate CPVT from LQTSCPVT is a LQTS mimicker.1

As many as 30% of CPVT patients have beenAs many as 30% of CPVT patients have been misdiagnosed as having “Long QT with normal QTc.”2,3

Genotyping Family Members of Known Probands Is Essential to Risk Management

All first-degree relatives, regardless of age, should be genotyped for the proband’s gene mutation(s).1,2,3

An asymptomatic parent with an LQTS mutation has a high probability of having children at risk for cardiac events.1

Approximately 33% of untreated siblings carry the proband’s gene mutation(s) and will have a cardiac event by 40 years of age.2

References: 1. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-533. 2. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001;104:557-562. 3. 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 death. J Am Coll Cardiol. 2006;48:1065-1102.


CASE A 12 year old boy passes out while swimming. He is appropriately resuscitated. The QTc on the ECG is 455 msec(indeterminate). Genetic testing comes back positive for long QT type 1type 1. » Subsequent genetic testing in his 8 year old sibling is positive

but negative in the 6 year old sibling. Parents also undergo testing and the mother is found to be a carrier. Genetic testing in this scenario was helpful for which of the following?

A. The 12 year old boyB Th 8 ld ibliB. The 8 year old siblingC. The 6 year old siblingD. Future offspring off all 3 childrenE. The parents

Index Case (12 year old)Probability of LQTS: » intermediate (Schwartz Score: 3)» intermediate (Schwartz Score: 3)» High with genetic testing

Therapy: » Initiate beta blockers but no need for ICD

Prevention: » Limit strenuous activities» Limit strenuous activities.

Prognosis: » good

Helpful: » yes


8 year old siblingProbability of LQTS:» intermediate (Schwartz Score: 2)» High with genetic testing (Positive family history and» High with genetic testing (Positive family history and

genotype positive)

Therapy: » Initiate beta blockers but no need for ICD

Prevention: » Limit strenuous activities.

P iPrognosis: » good

Helpful: » yes

6 year old siblingProbability of LQTS: » intermediate (Schwartz Score: 2)» Low with genetic testing (Positive family history» Low with genetic testing (Positive family history

and genotype negative)

Therapy: » No need to initiate beta blockers or ICD

Prevention: » No limitations

Prognosis:Prognosis: » good

Helpful: » yes


Future offspring off all 3 children

Probability of LQTS: » Depends on genetic test of parent

Recommendation» genetic testing for all offspring of genotype

positive subjects but not of genotype negative subjectsnegative subjects.

Helpful: » yes

The ParentsProbability of LQTS: » High in mother» Low in father

Recommend » genetic testing for all siblings of mother but

not of father.Therapy: » Initiate beta blockers but no need for ICD» Initiate beta blockers but no need for ICD

Prognosis: » good

Helpful: » yes


On 15 February 2006, 14 year old Shauna Stuewe was lost to Sudden Cardiac Arrest (SCA). An accomplished Gymnast and talented cheerleader, Shauna was both physically fit and the picture of health at the time her death.Shauna had been seen by a Pediatric Cardiologist who performed various tests including EKGs, Echocardiogram and Holter Monitor and concluded that Shauna was in good health, no further cardiac evaluation was needed and no restrictions were placed on herevaluation was needed and no restrictions were placed on her activities.Genetic autopsy testing on Shauna later revealed a gene mutation for CPVT.Her younger sister, who was also completely asympyomatic and an athlete, was subsequently found to be positive for CPVT by genetic testing. She now has an ICD.

The Role of Genetic Testing


Questions

Concerns with genetic testing

Cost: Cost» Make testing less expensive» bundle all channelopathy tests into one test.

Insurability» Universal insurance for all

Psychological trauma to families» Availability of genetic councilors

False positives and false negatives» Improve sensitivity and specificity of test

Significance of rare genotypes» Increase awareness of clinical significance of rare genotypes


Test YieldChannelopathy Sensitivity

Long QT Syndrome (LQTS) 75%

Brugada Syndrome 15-20%

CatecholaminergicPolymorphic Ventricular Tachycardia (CPVT)

50-55%

Documents

Genetic Testing is a Blessing: Cardiac Channelopathies Batra Pro Debate 12 15 pm.pdfcheerleader, Shauna was both physically fit and the picture of health at the time her death. zShauna