Risk of Life-Threatening Cardiac Events in Patients with Genotype- Confirmed Long-QT Syndrome and a Normal-Range QTc Ilan Goldenberg, MD,* Samuel Horr, MA,* Arthur J. Moss, MD,* Coeli M. Lopes, PhD,† Alon Barsheshet, MD, * Scott McNitt, MS, * Wojciech Zareba, MD,* PhD, Mark L. Andrews, BBA,* Jennifer L. Robinson, MS,* Emanuela H. Locati, MD,‡ Michael J. Ackerman, MD, PhD,§ Jesaia Benhorin, MD,¶ Elizabeth S. Kaufman, MD,║Carlo Napolitano, MD,# Pyotr G. Platonov, MD,** PhD, Silvia G. Priori, MD, PhD, # Ming Qi, MD,†† Peter J. Schwartz, MD,‡‡ Wataru Shimizu, MD, PhD,§§ Jeffrey A. Towbin, MD,¶¶ G. Michael Vincent, MD, ## Arthur A.M. Wilde MD, PhD,*** Li Zhang, MD.## From the *Cardiology Division of the Department of Medicine and the †Cardiovascular Research Institute and ††Pathology, University of Rochester Medical Center, Rochester, NY; ‡Cardiovascular Department De Gasperis, Niguarda Hospital, Milan, Italy; ¶Bikur Cholim Hospital, University of Jerusalem, Jerusalem, Israel; §Departments of Medicine, Pediatrics, and Molecular Pharmacology &Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic College of Medicine, Rochester, Minn;║The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; #Molecular Cardiology, Fondazione S. Maugeri-University of Pavia, Pavia, Italy and Leon Charney Division of Cardiology, New York University School of Medicine; the ‡‡Department of Cardiology, Fondazione Policlinico S. Matteo IRCCS and University of Pavia, Italy; the **Department of Cardiology, Lund University, Lund, Sweden; the §§Division of Cardiology, Department of Internal Medicine National Cardiovascular Center, Suita, Japan; the ¶¶Department of Pediatric Cardiology, Baylor College of Medicine, Houston, Tex; the ***Department of Cardiology Academic Medical Center, Amsterdam, the Netherlands; and the ##Department of Medicine University of Utah School of Medicine, Salt Lake City. Academic Medical Center, Amsterdam
Transcript
Risk of Life-Threatening Cardiac Events in Patients with Genotype-Confirmed Long-QT
Syndrome and a Normal-Range QTcIlan Goldenberg, MD,* Samuel Horr, MA,* Arthur J. Moss, MD,* Coeli M. Lopes, PhD,† Alon Barsheshet, MD, * Scott McNitt, MS, * Wojciech Zareba, MD,* PhD, Mark L. Andrews, BBA,* Jennifer L. Robinson, MS,* Emanuela H. Locati, MD,‡ Michael J. Ackerman, MD, PhD,§ Jesaia Benhorin, MD,¶ Elizabeth S. Kaufman, MD,║Carlo Napolitano, MD,# Pyotr G. Platonov, MD,** PhD, Silvia G. Priori, MD, PhD, # Ming Qi, MD,†† Peter J. Schwartz, MD,‡‡ Wataru Shimizu, MD, PhD,§§ Jeffrey A. Towbin, MD,¶¶ G. Michael Vincent, MD, ## Arthur A.M. Wilde MD, PhD,*** Li Zhang, MD.##
From the *Cardiology Division of the Department of Medicine and the †Cardiovascular Research Institute and ††Pathology, University of Rochester Medical Center, Rochester, NY; ‡Cardiovascular Department De Gasperis, Niguarda Hospital, Milan, Italy; ¶Bikur Cholim Hospital, University of Jerusalem, Jerusalem, Israel; §Departments of Medicine, Pediatrics, and Molecular Pharmacology &Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic College of Medicine, Rochester, Minn;║The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; #Molecular Cardiology, Fondazione S. Maugeri-University of Pavia, Pavia, Italy and Leon Charney Division of Cardiology, New York University School of Medicine; the ‡‡Department of Cardiology, Fondazione Policlinico S. Matteo IRCCS and University of Pavia, Italy; the **Department of Cardiology, Lund University, Lund, Sweden; the §§Division of Cardiology, Department of Internal Medicine National Cardiovascular Center, Suita, Japan; the ¶¶Department of Pediatric Cardiology, Baylor College of Medicine, Houston, Tex; the ***Department of Cardiology Academic Medical Center, Amsterdam, the Netherlands; and the ##Department of Medicine University of Utah School of Medicine, Salt Lake City.Academic Medical Center, Amsterdam
Presenter Disclosure Information
DISCLOSURE INFORMATIONThe following relationships exist related to this presentation:
The LQTS Registry is supported by research grants HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, Md.
Ilan Goldenberg, MDRisk of Life-Threatening Cardiac Events in Patients with Genotype-
Confirmed Long-QT Syndrome and a Normal-Range QTc
J Am Coll Cardiol 2010;57:51-59
Background
CURRENT STATUS
12 identified LQTS genotypes (>500 mutations)
Most frequent clinical types (LQT1-3):LQT1 (43%)LQT2 (45%)LQT3 (7%)
LQT4-12 make up less than 5% of cases
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LQTS Phenotype
Expressed by:QTc:
QTc ≥450 msec
Events: syncope, aborted cardiac arrest, SCD
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Clinical Course and Risk Stratification
Studies comprised mainly LQTS pts with QTc ≥450 msec
Clinical factors (QTc duration, age-gender interactions) in this population
No specific data regarding clinical course and risk factors in LQTS pts with normal QTc (referred to as: phenotype-negative LQTS or concealed LQTS)
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Mutation-Specific Risk Factors in LQTSMutation-Specific Risk Factors in LQTSMutation-Specific Risk Factors in LQTSMutation-Specific Risk Factors in LQTS
Moss et al. Circulation 2007Moss et al. Circulation 2007
KCNQ1
SCN5A
Study Hypothesis
We hypothesized that genetic factors and mutation characteristics may help identify high-risk LQTS patients who do not exhibit the phenotypic QTc prolongation of the disease
J Am Coll Cardiol 2010;57:51-59
Study Purpose
Assess the risk of life-threatening events among LQT1-3 pts with normal-range QTc
Identify specific clinical and genetic risk factors for life-threatening cardiac events in this population
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Methods
Study Population: Inclusion Criteria
3,386 genotyped subjects from proband identified LQT1-3 familiesInternational LQTS Registry:
US (n=2630)Denmark (n=90)Italy (n=28)Israel (n=25)Sweden (n=17)
Distribution of QTc Duration in Genotype-Positive Patients
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Unaffected Family Members
(n=1525)
LQTS and Normal-Range QTc
(n=469)
LQTS and Prolonged QTc
(n=1392)
Female 52% 48% 61%*
QTc
Median 420 msec 420 msec 490 msec
Mean 412 msec 419 msec 501 msec
Genotype
LQT1 NA 40% 39%
LQT2 NA 45% 47%
LQT3 NA 16% 14%
Mutation
TM-MS NA 35% 43%
P < 0.05
Baseline Characteristics
J Am Coll Cardiol 2010;57:51-59
Unaffected Family Members
(n=1525)
LQTS and Normal-Range QTc
(n=469)
LQTS and Prolonged QTc
(n=1392)
Therapies
Beta-blockers 6 % 38 % 54 %
Pacemaker 0.3 % 0.6 % 5 %
LCSD 0.1 % 0.2 % 1.4 %
ICD 0.6 % 6 14 %
Events
Syncope 10% 21% 40%
ACA 0.2 % 1.3 % 8.4 %
SCD 0.1 % 1.5 % 4.4 %
ACA/SCD 0.3% 2.8% 11.3%
P < 0.05
Therapies and Events during FU
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Gen+/QTc >440msec
Probability of ACA/SCD by Genotype/QTc Category
e.+/QTc>440
Ge.+/QTc≤440
Rate of ACA/SCD by Genotype/QTc Category
LQTS/prolonged QTc
LQTS/normal-range QTc
Unaffected controls
Fig. 2
LQTS prolonged QTc
LQTS normal-range QTc
Unaffected family members
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End Point: ACA/SCD
Risk-Group HR P-value
LQTS and Prolonged QTc vs.Unaffected family members
36.53 <0.001
LQTS and Prolonged QTc vs.Unaffected family members
10.25 <0.001
LQTS and Prolonged QTc vs.LQTS/Normal-range QTc
3.57 <0.001
*Adjusted for gender and time-dependent beta-blocker therapy
Multivariate Analysis: Total Population*
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LQTS/Normal-Range QTc LQTS/Prolonged QTc
Risk Group HR P-value HR P-value P-value for interaction
Gender
Female >13 yrs 1.32 0.64 1.90 0.002 0.53
Gender
LQT1 vs. LQT2 9.88 0.03 0.53 0.002 0.006
LQT3 vs. LQT2 8.04 0.07 1.07 0.77 0.08
Mutation
TM-MS 6.32 0.006 1.24 0.22 0.02
QTc
Per 10 msec inc 1.20 0.35 1.08 <0.001 0.58
>median vs. ≤median 1.03 0.95 2.96 <0.001 NA
*All findings were further adjusted for time-dependent beta-blocker therapy and family history of sudden cardiac death
Multivariate Analysis: Risk Factors for ACA/SCD*
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Fig. 3A
Rate of ACA/SCD in Patients with Normal-Range QTc by Mutation Location-type
Probability of ACA/SCD in LQTS Pts with a Normal-Range QTc by Mutation Location/Type
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Fig. 3B
Rate of ACA/SCD in Patients with Prolonged QTc by Mutation Location-type
Probability of ACA/SCD in LQTS Pts with Prolonged QTc by Mutation Location/Type
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Fig. 4A
Fig. 4B
A: Baseline ECG (QTc = 410 msec)
B: Development of Polymorphic VTFig. 4C
C: After initiation of beta-blocker and ICD therapy
Development of Polymorphic VT in an LQT1 Patients with Normal-Range QTc
Fig. 3B
Rate of ACA/SCD in Patients with Prolonged QTc by Mutation Location-type
Probability of ACA/SCD in LQTS Pts with Prolonged QTc by Mutation Location/Type
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Fig. 3B
Rate of ACA/SCD in Patients with Prolonged QTc by Mutation Location-type
Probability of ACA/SCD in LQTS Pts with Prolonged QTc by Mutation Location/Type
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Conclusions
Carriers of the LQT1-3 genotypes exhibit a wide QTc distribution25% have normal-range QTc Rate of ACA or SCD in Gen+/QTc≤440 msec
Relatively low (4% from birth through age 40 yrs)>10-fold risk increase compared with unaffected family members
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Clinical Implications
Risk assessment among phenotype-negative family members of LQTS probands should include genetic testing, Genetic data may be used to identify phenotype-negative patients with increased risk for fatal ventricular tachyarrhythmias LQTS patients with a normal-range QTc and a high-risk profile (i.e. LQT1 and LQT3 with TM-MS mutations) should receive similar management as phenotype-positive LQTS patientsLQTS patients with a normal-range QTc and a low risk profile (i.e. concealed LQT2 and non-transmembrane-missense LQT1 and LQT3) may need of only preventative health recommendations such as QT drug avoidance.
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Clinical ImplicationsDistinct predictors of life-threatening event among LQTS pts with normal and prolonged QTc: LQTS with normal-range QTc:
