The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michael J Ackerman - One of the best experts on this subject based on the ideXlab platform.
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management of congenital Long QT Syndrome commentary from the experts
Circulation-arrhythmia and Electrophysiology, 2021Co-Authors: Elizabeth S Kaufman, Michael J Ackerman, Lee L Eckhardt, Peter F Aziz, Elijah R Behr, Marina Cerrone, Mina K Chung, Michael J Cutler, Susan P Etheridge, Andrew D KrahnAbstract:While published guidelines are useful in the care of patients with Long-QT Syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in Long-QT Syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
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mexiletine shortens the QT interval in patients with potassium channel mediated type 2 Long QT Syndrome
Circulation-arrhythmia and Electrophysiology, 2019Co-Authors: Martijn J Bos, Peter J Schwartz, Lia Crotti, Federica Dagradi, Ram K Rohatgi, Silvia Castelletti, Michael J AckermanAbstract:Background: Long QT Syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel bl...
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the genetic architecture of Long QT Syndrome a critical reappraisal
Trends in Cardiovascular Medicine, 2018Co-Authors: John R Giudicessi, Arthur A M Wilde, Michael J AckermanAbstract:Collectively, the completion of the Human Genome Project and subsequent development of high-throughput next-generation sequencing methodologies have revolutionized genomic research. However, the rapid sequencing and analysis of thousands upon thousands of human exomes and genomes has taught us that most genes, including those known to cause heritable cardiovascular disorders such as Long QT Syndrome, harbor an unexpected background rate of rare, and presumably innocuous, non-synonymous genetic variation. In this Review, we aim to reappraise the genetic architecture underlying both the acquired and congenital forms of Long QT Syndrome by examining how the clinical phenotype associated with and background genetic variation in Long QT Syndrome-susceptibility genes impacts the clinical validity of existing gene-disease associations and the variant classification and reporting strategies that serve as the foundation for diagnostic Long QT Syndrome genetic testing.
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classification and reporting of potentially proarrhythmic common genetic variation in Long QT Syndrome genetic testing
Circulation, 2018Co-Authors: John R Giudicessi, Arthur A M Wilde, Dan M Roden, Michael J AckermanAbstract:The acquired and congenital forms of Long QT Syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval proLongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital Long QT Syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital Long QT Syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired Long QT Syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.
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loss of function kcne2 variants true monogenic culprits of Long QT Syndrome or proarrhythmic variants requiring secondary provocation
Circulation-arrhythmia and Electrophysiology, 2017Co-Authors: Jason D Roberts, Arthur J. Moss, Michael J Ackerman, Rafik Tadros, Andrew D Krahn, Ram K Rohatgi, Babak Nazer, Brenda Gerull, Shubhayan Sanatani, Yanushi D WijeyeratneAbstract:Background—Insight into type 6 Long-QT Syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phen...
Peter J Schwartz - One of the best experts on this subject based on the ideXlab platform.
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mexiletine shortens the QT interval in patients with potassium channel mediated type 2 Long QT Syndrome
Circulation-arrhythmia and Electrophysiology, 2019Co-Authors: Martijn J Bos, Peter J Schwartz, Lia Crotti, Federica Dagradi, Ram K Rohatgi, Silvia Castelletti, Michael J AckermanAbstract:Background: Long QT Syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel bl...
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autonomic control of heart rate and QT interval variability influences arrhythmic risk in Long QT Syndrome type 1
Journal of the American College of Cardiology, 2015Co-Authors: Alberto Porta, Lia Crotti, Althea Goosen, Giulia Girardengo, Vlasta Bari, Alfred L George, Paul A Brink, Peter J SchwartzAbstract:AbstractBackground: A puzzling feature of the Long QT Syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes.Objectives: This study te...
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QTc behavior during exercise and genetic testing for the Long QT Syndrome
Circulation, 2011Co-Authors: Peter J Schwartz, Lia CrottiAbstract:The quest to facilitate the diagnosis of the Long-QT Syndrome (LQTS) and even to predict genotype is neverending. The study by Sy et al1 published in the current issue of Circulation adds a new piece to the puzzle and has the potential to be very useful. Article see p 2187 Since the early days,2 diagnosis of the Long-QT Syndrome (LQTS) has undergone several levels of progressive upgrade. Initially, the diagnosis was made only in the presence of multiple factors, such as very bizarre T waves and marked proLongations of the QT interval in a child or teenager or abrupt loss of consciousness during emotional or physical stress, and it also required one of the few medical doctors who had heard about LQTS. The first attempt to provide diagnostic criteria for LQTS came in 19853 and, in their simplicity, they are still useful now for a first assessment (Table 1). As the disease became better known, as was bound to happen given its prevalence (1 in 2 000),4,5 a new set of more specific diagnostic criteria to discriminate between subjects likely or unlikely to be affected by LQTS was proposed and provided a quantitative score.6 View this table: Table 1. 1985 LQTS Diagnostic Criteria Those criteria, subsequently referred to as the “Schwartz criteria,” were developed before the genetic revolution, which has progressively led to the identification of 13 LQTS disease-causing genes.7 As a consequence, a lot of weight was placed on the actual duration of the QT interval. By the early 1990s, it had been recognized8 that the highest risk was for patients who had already suffered 1 cardiac event. It was thus essential not to miss the diagnosis in these patients; hence, weight was given to previous symptoms. Also, it was obvious that the disease had …
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prevalence of the congenital Long QT Syndrome
Circulation, 2009Co-Authors: Peter J Schwartz, Lia Crotti, Roberto Insolia, Alessandra Besana, Marco Strambabadiale, Matteo Pedrazzini, Giuliano Bosi, Fulvio Gabbarini, Karine Goulene, Savina MannarinoAbstract:Background— The prevalence of genetic arrhythmogenic diseases is unknown. For the Long-QT Syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS. Methods and Results— In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of gen...
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clinical implications for patients with Long QT Syndrome who experience a cardiac event during infancy
Journal of the American College of Cardiology, 2009Co-Authors: Carla Spazzolini, Arthur J. Moss, Jamie Mullally, Peter J Schwartz, Scott Mcnitt, Gregory M Ouellet, Thomas Fugate, Ilan Goldenberg, Christian Jons, Wojciech ZarebaAbstract:Objectives This study was designed to evaluate the clinical and prognostic aspects of Long QT Syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy). Background The clinical implications for patients with Long QT Syndrome who experience cardiac events in infancy have not been studied previously. Methods The study population of 3,323 patients with QT interval corrected for heart rate (QTc) ≥450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life. Results The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc ≥500 ms, heart rate ≤100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p Conclusions Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset.
Lia Crotti - One of the best experts on this subject based on the ideXlab platform.
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transethnic genome wide association study provides insights in the genetic architecture and heritability of Long QT Syndrome
Circulation, 2020Co-Authors: Najim Lahrouchi, Lia Crotti, Yuka Mizusawa, Rafik Tadros, Pieter G Postema, Leander Beekman, Roddy Walsh, Kanae Hasegawa, Julien Barc, Marko ErnstingAbstract:Background: Long QT Syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified...
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mexiletine shortens the QT interval in patients with potassium channel mediated type 2 Long QT Syndrome
Circulation-arrhythmia and Electrophysiology, 2019Co-Authors: Martijn J Bos, Peter J Schwartz, Lia Crotti, Federica Dagradi, Ram K Rohatgi, Silvia Castelletti, Michael J AckermanAbstract:Background: Long QT Syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel bl...
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clinical aspects of type 3 Long QT Syndrome an international multicenter study
Circulation, 2016Co-Authors: Arthur A M Wilde, Arthur J. Moss, Carla Spazzolini, Jesaia Benhorin, Elizabeth S Kaufman, Jeffrey A Towbin, Wataru Shimizu, Derick R Peterson, Coeli M Lopes, Lia CrottiAbstract:Background:Risk stratification in patients with type 3 Long-QT Syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a la...
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the genetics underlying acquired Long QT Syndrome impact for genetic screening
European Heart Journal, 2016Co-Authors: Hideki Itoh, Carla Spazzolini, Lia Crotti, Veronique Fressart, Takeshi Aiba, I Denjoy, Kenshi Hayashi, Tadashi Nakajima, Seiko OhnoAbstract:Aims Acquired Long QT Syndrome (aLQTS) exhibits QT proLongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains proLonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors. Methods and results We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated ‘true aLQTS’ (QTc within normal limits) or ‘unmasked cLQTS’ (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital Long QT Syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and Longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in ‘true aLQTS’, KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7–41%] vs. 64% [95% CI 43–82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations. Conclusion A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.
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autonomic control of heart rate and QT interval variability influences arrhythmic risk in Long QT Syndrome type 1
Journal of the American College of Cardiology, 2015Co-Authors: Alberto Porta, Lia Crotti, Althea Goosen, Giulia Girardengo, Vlasta Bari, Alfred L George, Paul A Brink, Peter J SchwartzAbstract:AbstractBackground: A puzzling feature of the Long QT Syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes.Objectives: This study te...
Arthur J. Moss - One of the best experts on this subject based on the ideXlab platform.
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loss of function kcne2 variants true monogenic culprits of Long QT Syndrome or proarrhythmic variants requiring secondary provocation
Circulation-arrhythmia and Electrophysiology, 2017Co-Authors: Jason D Roberts, Arthur J. Moss, Michael J Ackerman, Rafik Tadros, Andrew D Krahn, Ram K Rohatgi, Babak Nazer, Brenda Gerull, Shubhayan Sanatani, Yanushi D WijeyeratneAbstract:Background—Insight into type 6 Long-QT Syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phen...
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clinical aspects of type 3 Long QT Syndrome an international multicenter study
Circulation, 2016Co-Authors: Arthur A M Wilde, Arthur J. Moss, Carla Spazzolini, Jesaia Benhorin, Elizabeth S Kaufman, Jeffrey A Towbin, Wataru Shimizu, Derick R Peterson, Coeli M Lopes, Lia CrottiAbstract:Background:Risk stratification in patients with type 3 Long-QT Syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a la...
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light phase restricted feeding slows basal heart rate to exaggerate the type 3 Long QT Syndrome phenotype in mice
American Journal of Physiology-heart and Circulatory Physiology, 2014Co-Authors: Elizabeth A Schroder, Arthur J. Moss, Don E Burgess, Cody L Manning, Yihua Zhao, Abhijit Patwardhan, Claude S Elayi, Karyn A Esser, Brian P DelisleAbstract:Long QT Syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) int...
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clinical implications for patients with Long QT Syndrome who experience a cardiac event during infancy
Journal of the American College of Cardiology, 2009Co-Authors: Carla Spazzolini, Arthur J. Moss, Jamie Mullally, Peter J Schwartz, Scott Mcnitt, Gregory M Ouellet, Thomas Fugate, Ilan Goldenberg, Christian Jons, Wojciech ZarebaAbstract:Objectives This study was designed to evaluate the clinical and prognostic aspects of Long QT Syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy). Background The clinical implications for patients with Long QT Syndrome who experience cardiac events in infancy have not been studied previously. Methods The study population of 3,323 patients with QT interval corrected for heart rate (QTc) ≥450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life. Results The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc ≥500 ms, heart rate ≤100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p Conclusions Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset.
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Long QT Syndrome
Current Problems in Cardiology, 2008Co-Authors: Ilan Goldenberg, Wojciech Zareba, Arthur J. MossAbstract:The hereditary Long QT Syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. The diagnosis of this genetic disorder relies on a constellation of electrocardiographic, clinical, and genetic factors. Accumulating data from recent studies indicate that the clinical course of affected LQTS patients is time-dependent and age-specific, demonstrating important gender differences among age groups. Risk assessment should consider age-gender interactions, prior syncopal history, QT-interval duration, and genetic factors. Beta-blockers constitute the mainstay therapy for LQTS, while left cardiac sympathetic denervation and implantation of a cardioverter defibrillator should be considered in patients who remain symptomatic despite beta-blocker therapy. Current and ongoing studies are also evaluating genotype-specific therapies that may reduce the risk for life-threatening cardiac events in high-risk LQTS patients.
Corey L Anderson - One of the best experts on this subject based on the ideXlab platform.
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Long QT Syndrome kcnh2 variant induces herg1a 1b subunit imbalance in patient specific induced pluripotent stem cell derived cardiomyocytes
Circulation-arrhythmia and Electrophysiology, 2021Co-Authors: Li Feng, Corey L Anderson, Jianhua Zhang, Changhwan Lee, Gina Kim, Fang Liu, Andrew J Petersen, Evi Lim, Kate M Orland, Gail A RobertsonAbstract:Background - Inherited Long QT Syndrome type 2 (LQT2) results from variants in the KCNH2 gene encoding the hERG1 potassium channel. Two main isoforms, hERG1a and hERG1b, assemble to form tetrameric...
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large scale mutational analysis of kv11 1 reveals molecular insights into type 2 Long QT Syndrome
Nature Communications, 2014Co-Authors: Corey L Anderson, Catherine E Kuzmicki, Ryan R Childs, Caleb J Hintz, Brian P Delisle, Craig T JanuaryAbstract:Type 2 Long QT Syndrome is a cardiac disease associated with hundreds of individual mutations within the Kv11.1 potassium channel. Here, the authors systematically investigate the trafficking defects associated with different types of Kv11.1 mutations and to what extent they can be corrected pharmacologically.
