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1. Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families

Author: Maria‐Christina Kotta, Margherita Torchio, Pauline Bayliss, Marta C. Cohen, Oliver Quarrell, Nigel Wheeldon, Tamás Marton, Davide Gentilini, Lia Crotti, Robert C. Coombs, and Peter J. Schwartz
Subjects: channelopathies, molecular autopsy, sudden infant death syndrome, sudden unexplained death in childhood, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy‐seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive‐evidence arrhythmia‐associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double‐blind review of clinical‐genetic data established genotype–phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra‐rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive‐evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype–phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive‐evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.
Published: 2023
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2. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

Author: Arthur A. M. Wilde, Christopher Semsarian, Manlio F. Márquez, Alireza Sepehri Shamloo, Michael J. Ackerman, Euan A. Ashley, Back Sternick Eduardo, Héctor Barajas‐Martinez, Elijah R. Behr, Connie R. Bezzina, Jeroen Breckpot, Philippe Charron, Priya Chockalingam, Lia Crotti, Michael H. Gollob, Steven Lubitz, Naomasa Makita, Seiko Ohno, Martín Ortiz‐Genga, Luciana Sacilotto, Eric Schulze‐Bahr, Wataru Shimizu, Nona Sotoodehnia, Rafik Tadros, James S. Ware, David S. Winlaw, Elizabeth S. Kaufman, Takeshi Aiba, Andreas Bollmann, Jong‐Il Choi, Aarti Dalal, Francisco Darrieux, John Giudicessi, Mariana Guerchicoff, Kui Hong, Andrew D. Krahn, Ciorsti Mac Intyre, Judith A. Mackall, Lluís Mont, Carlo Napolitano, Pablo Ochoa Juan, Petr Peichl, Alexandre C. Pereira, Peter J. Schwartz, Jon Skinner, Christoph Stellbrink, Jacob Tfelt‐Hansen, and Thomas Deneke
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Published: 2022
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3. Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

Author: Luca Sala, Vladislav Leonov, Manuela Mura, Federica Giannetti, Aleksandr Khudiakov, Alessandra Moretti, Lia Crotti, Massimiliano Gnecchi, and Peter J. Schwartz
Subjects: Long QT Syndrome, COVID-19, hydroxychloroquine, induced pluripotent stem cells, safety pharmacology, precision medicine, Physiology, QP1-981
Abstract: In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring is challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrated that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation and halted the beating at high concentration due to the combined effect of HCQ on multiple ion currents. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs. asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine.
Published: 2022
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4. Rube Stories and Paradigmatic Crimes as Narrative Modulators at Thresholds of Cultural Change

Author: Peter J. Schwartz
Subjects: Media archaeology, Narrative theory, Early cinema, Crime stories, Literary morphology, Language and Literature
Abstract: This essay investigates two species of a larger genus of narrative (“narrative modulators”) characterized by its function as a sort of compromise formation addressing recurrent anxieties and tensions at major thresholds of cultural change. One of these is a story type linked with cinema’s early reception: that of the “credulous spectator,” figured in early film and film lore as the country bumpkin or “rube” who, misperceiving the projected image as real, runs from the oncoming train or from the wet of onscreen waves or tries to enter the story; I extend this type beyond cinema to include precinematic literary examples. I’ve coined the term “paradigmatic crimes” to describe stories of criminal acts used to address pressing cultural concerns at given historical junctures as a second type of “narrative modulator.” As with “rube stories,” what unifies “paradigmatic crimes” as a story type is their specific function as “narrative modulators” in moments of cultural change. My hypothesis is that functionally similar stories appear at structurally comparable thresholds of media change in various cultures at various times, and that the similarities are to be explained mainly morphologically (i.e. mainly at the abstract level of their capacity to modulate cultural change).
Published: 2021

5. Autonomic Control of the Heart and Its Clinical Impact. A Personal Perspective

Author: Maria Teresa La Rovere, Alberto Porta, and Peter J. Schwartz
Subjects: heart rate variability, QT interval, baroreflex sensitivity, autonomic nervous system, sympathetic nervous system, vagal activity, Physiology, QP1-981
Abstract: This essay covers several aspects of the autonomic control of the heart, all relevant to cardiovascular pathophysiology with a direct impact on clinical outcomes. Ischemic heart disease, heart failure, channelopathies, and life-threatening arrhythmias are in the picture. Beginning with an overview on some of the events that marked the oscillations in the medical interest for the autonomic nervous system, our text explores specific areas, including experimental and clinical work focused on understanding the different roles of tonic and reflex sympathetic and vagal activity. The role of the baroreceptors, not just for the direct control of circulation but also because of the clinical value of interpreting alterations (spontaneous or induced) in their function, is discussed. The importance of the autonomic nervous system for gaining insights on risk stratification and for providing specific antiarrhythmic protection is also considered. Examples are the interventions to decrease sympathetic activity and/or to increase vagal activity. The non-invasive analysis of the RR and QT intervals provides additional information. The three of us have collaborated in several studies and each of us contributes with very specific and independent areas of expertise. Here, we have focused on those areas to which we have directly contributed and hence speak with personal experience. This is not an attempt to provide a neutral and general overview on the autonomic nervous system; rather, it represents our effort to share and provide the readers with our own personal views matured after many years of research in this field.
Published: 2020
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6. Generation of the human induced pluripotent stem cell (hiPSC) line PSMi006-A from a patient affected by an autosomal recessive form of long QT syndrome type 1

Author: Manuela Mura, Francesca Bastaroli, Marzia Corli, Monia Ginevrino, Federica Calabrò, Marina Boni, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 40 years old female patient homozygous for the mutation c.535 G > A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1). The hiPSCs, generated using classical approach of the four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and differentiate into cell lineages of all three germ layers: endoderm, mesoderm and ectoderm. Keywords: Endoderm, Mesoderm, Ectoderm
Published: 2020
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7. Generation of the human induced pluripotent stem cell (hiPSC) line PSMi003-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1

Author: Manuela Mura, Monia Ginevrino, Rita Zappatore, Federica Pisano, Marina Boni, Silvia Castelletti, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 51 years old female patient homozygous for the mutation c.535 G>A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1), not associated with deafness. The hiPSCs, generated using four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC, are pluripotent and can differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).
Published: 2018
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8. Generation of the human induced pluripotent stem cell (hiPSC) line PSMi002-A from a patient affected by the Jervell and Lange-Nielsen syndrome and carrier of two compound heterozygous mutations on the KCNQ1 gene

Author: Manuela Mura, Yee-ki Lee, Monia Ginevrino, Rita Zappatore, Federica Pisano, Marina Boni, Federica Dagradi, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, Hung-Fat Tse, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We report the generation of human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a female patient carrier of the two compound heterozygous mutations c.568 C>T p.R190W (maternal allele), and c.1781 G>A p.R594Q (paternal allele) on the KCNQ1 gene, causing Jervell and Lange-Nielsen Syndrome (JLNS). To obtain hiPSCs, we used the classical approach of the four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC. The obtained hiPSC clones display pluripotent stem cell characteristics, and differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).
Published: 2018
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9. Generation of two human induced pluripotent stem cell (hiPSC) lines from a long QT syndrome South African founder population

Author: Manuela Mura, Federica Pisano, Manuela Stefanello, Monia Ginevrino, Marina Boni, Federica Calabrò, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, Paul A. Brink, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We generated PSMi001-A and PSMi008-A hiPSC lines from two individuals belonging to a South African (SA) founder population in which the malignant KCNQ1-A341V mutation cosegregates with the Long QT Syndrome (LQTS) phenotype. PSMi001-A was derived from an asymptomatic KCNQ1-A341V mutation carrier, whereas PSMi008-A was derived from a healthy non-mutation carrier, heterozygous for the minor variant rs16847548 on the NOS1AP gene, associated with QT prolongation in the general population, and with a greater risk for cardiac arrest in the affected members of the SA founder population. The hiPSCs, generated using the Yamanaka's retroviruses, display pluripotent stem cell features and trilineage differentiation potential.
Published: 2019
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10. Generation of the human induced pluripotent stem cell (hiPSC) line PSMi004-A from a carrier of the KCNQ1-R594Q mutation

Author: Manuela Mura, Yee-Ki Lee, Federica Pisano, Monia Ginevrino, Marina Boni, Federica Calabrò, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, Hung-Fat Tse, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a male carrier of the heterozygous mutation c.1781 G > A p.R594Q on the KCNQ1 gene. hiPSCs, generated using four retroviruses each encoding for OCT4, SOX2, KLF4 and cMYC, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).
Published: 2019
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11. Generation of the human induced pluripotent stem cell (hiPSC) line PSMi005-A from a patient carrying the KCNQ1-R190W mutation

Author: Manuela Mura, Yee-Ki Lee, Federica Pisano, Monia Ginevrino, Marina Boni, Federica Calabrò, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, Hung-Fat Tse, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a woman carrier of the heterozygous mutation c.568C > T p.R190W on the KCNQ1 gene. hiPSCs, obtained using four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).
Published: 2019
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12. Generation of the human induced pluripotent stem cell (hiPSC) line PSMi007-A from a Long QT Syndrome type 1 patient carrier of two common variants in the NOS1AP gene

Author: Manuela Mura, Federica Pisano, Manuela Stefanello, Monia Ginevrino, Marina Boni, Federica Calabrò, Lia Crotti, Enza Maria Valente, Peter J. Schwartz, Paul A. Brink, and Massimiliano Gnecchi
Subjects: Biology (General), QH301-705.5
Abstract: We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic Long QT Syndrome (LQTS) type 1 patient, belonging to a South African (SA) founder population segregating the heterozygous mutation c.1022C > T p.A341V on the KCNQ1 gene. The patient is also homozygous for the two minor variants rs4657139 and rs16847548 on the NOS1AP gene, associated with greater risk for cardiac arrest and sudden death in LQTS mutation carriers of the founder population. hiPSCs, obtained using four retroviruses encoding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).
Published: 2019
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13. Cardiac Sympathetic Denervation in Channelopathies

Author: Veronica Dusi, Gaetano Maria De Ferrari, Luigi Pugliese, and Peter J. Schwartz
Subjects: sudden cardiac death, cardiac sympathetic denervation, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, cardiac autonomic nervous system, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Left cardiac sympathetic denervation (LCSD) is a surgical antiadrenergic intervention with a strong antiarrhythmic effect, supported by preclinical as well as clinical data. The mechanism of action of LCSD in structurally normal hearts with increased arrhythmic susceptibility (such as those of patients with channelopathies) is not limited to the antagonism of acute catecholamines release in the heart. LCSD also conveys a strong anti-fibrillatory action that was first demonstrated over 40 years ago and provides the rationale for its use in almost any cardiac condition at increased risk of ventricular fibrillation. The molecular mechanisms involved in the final antiarrhythmic effect of LCSD turned out to be much broader than anticipated. Beside the vagotonic effect at different levels of the neuraxis, other new mechanisms have been recently proposed, such as the antagonism of neuronal remodeling, the antagonism of neuropeptide Y effects, and the correction of neuronal nitric oxide synthase (nNOS) imbalance. The beneficial effects of LCSD have never been associated with a detectable deterioration of cardiac performance. Finally, patients express a high degree of satisfaction with the procedure. In this review, we focus on the rationale, results and our personal approach to LCSD in patients with channelopathies such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia.
Published: 2019
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14. A Refined Multiscale Self-Entropy Approach for the Assessment of Cardiac Control Complexity: Application to Long QT Syndrome Type 1 Patients

Author: Vlasta Bari, Giulia Girardengo, Andrea Marchi, Beatrice De Maria, Paul A. Brink, Lia Crotti, Peter J. Schwartz, and Alberto Porta
Subjects: information storage, heart rate variability, QT interval, refined multiscale entropy, LQT1, corrected conditional entropy, KCNQ1-A341V mutation, autonomic nervous system, Science, Astrophysics, QB460-466, Physics, QC1-999
Abstract: The study proposes the contemporaneous assessment of conditional entropy (CE) and self-entropy (sE), being the two terms of the Shannon entropy (ShE) decomposition, as a function of the time scale via refined multiscale CE (RMSCE) and sE (RMSsE) with the aim at gaining insight into cardiac control in long QT syndrome type 1 (LQT1) patients featuring the KCNQ1-A341V mutation. CE was estimated via the corrected CE (CCE) and sE as the difference between the ShE and CCE. RMSCE and RMSsE were computed over the beat-to-beat series of heart period (HP) and QT interval derived from 24-hour Holter electrocardiographic recordings during daytime (DAY) and nighttime (NIGHT). LQT1 patients were subdivided into asymptomatic and symptomatic mutation carriers (AMCs and SMCs) according to the severity of symptoms and contrasted with non-mutation carriers (NMCs). We found that RMSCE and RMSsE carry non-redundant information, separate experimental conditions (i.e., DAY and NIGHT) within a given group and distinguish groups (i.e., NMC, AMC and SMC) assigned the experimental condition. Findings stress the importance of the joint evaluation of RMSCE and RMSsE over HP and QT variabilities to typify the state of the autonomic function and contribute to clarify differences between AMCs and SMCs.
Published: 2015
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15. Low-Pass Filtering Approach via Empirical Mode Decomposition Improves Short-Scale Entropy-Based Complexity Estimation of QT Interval Variability in Long QT Syndrome Type 1 Patients

Author: Vlasta Bari, Andrea Marchi, Beatrice De Maria, Giulia Girardengo, Alfred L. George, Paul A. Brink, Sergio Cerutti, Lia Crotti, Peter J. Schwartz, and Alberto Porta
Subjects: heart rate variability, LQT1, EMD, sample entropy, KCNQ1-A341V mutation, beta-blocker therapy, autonomic nervous system, cardiovascular control, Science, Astrophysics, QB460-466, Physics, QC1-999
Abstract: Entropy-based complexity of cardiovascular variability at short time scales is largely dependent on the noise and/or action of neural circuits operating at high frequencies. This study proposes a technique for canceling fast variations from cardiovascular variability, thus limiting the effect of these overwhelming influences on entropy-based complexity. The low-pass filtering approach is based on the computation of the fastest intrinsic mode function via empirical mode decomposition (EMD) and its subtraction from the original variability. Sample entropy was exploited to estimate complexity. The procedure was applied to heart period (HP) and QT (interval from Q-wave onset to T-wave end) variability derived from 24-hour Holter recordings in 14 non-mutation carriers (NMCs) and 34 mutation carriers (MCs) subdivided into 11 asymptomatic MCs (AMCs) and 23 symptomatic MCs (SMCs). All individuals belonged to the same family developing long QT syndrome type 1 (LQT1) via KCNQ1-A341V mutation. We found that complexity indexes computed over EMD-filtered QT variability differentiated AMCs from NMCs and detected the effect of beta-blocker therapy, while complexity indexes calculated over EMD-filtered HP variability separated AMCs from SMCs. The EMD-based filtering method enhanced features of the cardiovascular control that otherwise would have remained hidden by the dominant presence of noise and/or fast physiological variations, thus improving classification in LQT1.
Published: 2014
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16. The Ideological Antecedents of the First-Series Renminbi Worker-and-Peasant Banknote or What Mao Tse-tung May Have Owed to Dziga Vertov

Author: Peter J. Schwartz
Subjects: mao tse-tung, dziga vertov, alexander dovzhenko, socialist realism, lenin cult, mao cult, soviet silent cinema, propaganda, iconography, early film, Social Sciences
Abstract: This paper traces the history of an iconic Socialist Realist image—that of the worker, peasant, soldier, or leader viewed from below whilst gazing heroically into the symbolic dawn of a Socialist future—from its origins in mid-1920s Soviet Russia through its use on three banknotes in Communist China’s first renminbi series of 1949 to its effective dissolution in the iconography of Deng-era currency. It argues that this iconic type—familiar not only from Stalinist but also from Italian Fascist and German National Socialist imagery—arose initially as a consequence of the legitimation crisis provoked in the USSR by Lenin’s death in January 1924, and that it may have originated in cinema before spreading from there to photography and poster art. An examination especially of the film work of Dziga Vertov shows that the icon encodes in its visual syntax techniques of political, technological, and media pedagogy meant both to form the “new Soviet man” and to orient populations within a chain of symbolic identifications supporting the charismatic authority of their leaders. It is suggested that Mao’s documented decision to use this image on renminbi instead of his own otherwise ubiquitous portrait reflects a perception of the propagandistic value of this visual syntax, and that both Mao’s posthumous reappearance on Chinese currency and the icon’s transformation on fourth-series renminbi from class pairs gazing upward to ethnic pairs gazing laterally reflects, among other things, the Deng-era shift from a hieratic semantics of charismatic legitimation to a more sober strategy of legitimation by political and economic rationalization.
Published: 2014
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17. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

Author: Silvia G. Priori, MD, PhD, Arthur A. Wilde, MD, PhD, Minoru Horie, MD, PhD, Yongkeun Cho, MD, PhD, Elijah R. Behr, MA, MBBS, MD, FRCP, Charles Berul, MD, FHRS, CCDS, Nico Blom, MD, PhD, Josep Brugada, MD, PhD, Chern-En Chiang, MD, PhD, Heikki Huikuri, MD, Prince Kannankeril, MD, Andrew Krahn, MD, FHRS, Antoine Leenhardt, MD, Arthur Moss, MD, Peter J. Schwartz, Wataru Shimizu, MD, PhD, Gordon Tomaselli, MD, FHRS, and Cynthia Tracy, MD
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Published: 2014
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18. Executive Summary: HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

Author: Silvia G. Priori, MD, PhD, Arthur A. Wilde, MD, PhD, Minoru Horie, MD, PhD, Yongkeun Cho, MD, PhD, Elijah R. Behr, MA, MBBS, MD, FRCP, Charles Berul, MD, FHRS, CCDS, Nico Blom, MD, PhD, Josep Brugada, MD, PhD, Chern-En Chiang, MD, PhD, Heikki Huikuri, MD, Prince Kannankeril, MD, Andrew Krahn, MD, FHRS, Antoine Leenhardt, MD, Arthur Moss, MD, Peter J. Schwartz, MD, Wataru Shimizu, MD, PhD, Gordon Tomaselli, MD, FHRS, and Cynthia Tracy, MD
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Published: 2014
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19. Congenital Short QT Syndrome

Author: Lia Crotti, Erika Taravelli, Giulia Girardengo, and Peter J. Schwartz
Subjects: Short QT Syndrome, sudden cardiac death, channelopathies, ICD, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: The Short QT Syndrome is a recently described new genetic disorder, characterized by abnormally short QT interval, paroxysmal atrial fibrillation and life threatening ventricular arrhythmias. This autosomal dominant syndrome can afflict infants, children, or young adults; often a remarkable family background of cardiac sudden death is elucidated. At electrophysiological study, short atrial and ventricular refractory periods are found, with atrial fibrillation and polymorphic ventricular tachycardia easily induced by programmed electrical stimulation. Gain of function mutations in three genes encoding K+ channels have been identified, explaining the abbreviated repolarization seen in this condition: KCNH2 for Ikr (SQT1), KCNQ1 for Iks (SQT2) and KCNJ2 for Ik1 (SQT3). The currently suggested therapeutic strategy is an ICD implantation, although many concerns exist for asymptomatic patients, especially in pediatric age. Pharmacological treatment is still under evaluation; quinidine has shown to prolong QT and reduce the inducibility of ventricular arrhythmias, but awaits additional confirmatory clinical data.
Published: 2010

20. Practical issues in the management of the long QT syndrome: focus on diagnosis and therapy

Author: Peter J. Schwartz
Subjects: genetics, genotype-phenotype correlation, implantable cardioverter defibrillator, ion channels., left cardiac sympathetic denervation, long QT syndrome, Medicine
Abstract: The long QT syndrome (LQTS) is a leading cause of sudden death in the young. It is not as rare as previously assumed, given its established prevalence of 1:2,000 live births. It is characterised by prolongation of the QT interval and by the occurrence of syncope, due to torsades-des-pointes ventricular tachycardia, cardiac arrest and sudden death; these life-threatening cardiac events are usually, but not always, associated with physical or emotional stress. It is a genetic disorder, and knowledge of the genotype impacts significantly on management. Extremely effective therapies are available, which makes the existence of undiagnosed affected and symptomatic patients inexcusable. Indeed, mortality for properly treated patients has now declined to around 1% over a 10-year period. This review, aimed at the clinical cardiologist, discusses briefly the essential genetic information and focuses primarily on the main issues of diagnosis and therapy. One special point of interest is in the impact of genetics on clinical management and the potential medicolegal consequences of not pursuing genetic screening in the proband and hence in the family members.
Published: 2013
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21. Sudden infant death syndrome and cardiac channelopathies: from mechanisms to prevention of avoidable tragedies

Author: Peter J. Schwartz, Roberto Insolia, Cinzia Dossena, Elisa Mastantuono, and Alice Ghidoni
Subjects: SIDS, sudden infant death syndrome, post-neonatal mortality., Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: The sudden infant death syndrome (SIDS), with the load of mystery surrounding its causes and with the devastating impact on the affected families, remains the greatest contributor to post-neonatal mortality during the first year of life. Following a succinct review of the non-cardiac genetic factors, which have been associated with SIDS, we focus on the cardiac hypothesis for SIDS and specifically on those diseases produced by cardiac ion channel mutations, the so-called channelopathies. Special attention is devoted to the fact that these causes of SIDS, and especially the long QT syndrome, are preventable if diagnosed in time. This highlights the importance of neonatal ECG screening and carries a number of practical implications, including medico-legal considerations.
Published: 2011
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22. Long QT syndrome: from genetic basis to treatment

Author: Lia Crotti, Peter J. Schwartz, and Federica Dagradi
Subjects: long QT syndrome, sudden cardiac death, genetics, ICD., Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: The congenital long QT syndrome (LQTS) is a monogenic disorder, not as rare as it was originally estimated to be, mainly caused by mutations in genes encoding for ion channels. Molecular screening in this disease is part of the diagnostic process and this has already been recognized by current guidelines since 2006. However, very recently, two consensus documents have been published, with the recommendations for the use of genetic testing in the clinical evaluation of genetically transmitted arrhythmogenic diseases. Therefore, we devoted a specific section of the present review to the discussion of these two documents in relation to LQTS. The clinical presentation of the disease is typically characterized by a prolongation of the QT interval on the electrocardiogram (ECG) and by the occurrence of syncope or cardiac arrest, mainly precipitated by sympathetic activation. While the diagnosis of typical cases it is quite easy, borderline cases can be quite challenging and therefore the availability of diagnostic criteria is very useful to support the diagnostic process. Very recently, the LQTS diagnostic criteria have been updated and they are presented in the current review. Finally, the clinical management of LQTS patients is presented together with a schematic flow-chart and recent data coming from the LQTS-ICD European registry are illustrated. The last part of the review is dedicated at future perspectives and latest results on modifier genes and stem cells are presented.
Published: 2011
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23. Frequency Domain Heart Period and QT Interval Variability Markers Are Linked to Arrhythmic Risk in Long QT Syndrome Type 2.

Author: Vlasta Bari, Giulia Girardengo, Beatrice De Maria, Beatrice Cairo, Lia Crotti, Peter J. Schwartz, and Alberto Porta
Published: 2020
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24. Multiscale Complexity Analysis of Short QT Interval Variability Series Stratifies the Arrhythmic Risk of Long QT Syndrome Type 1 Patients.

Author: Vlasta Bari, Beatrice De Maria, Giulia Girardengo, Emanuele Vaini, Beatrice Cairo, Lia Crotti, Paul A. Brink, Peter J. Schwartz, and Alberto Porta
Published: 2018
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25. Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

Author: Luca Sala, Massimiliano Gnecchi, and Peter J Schwartz
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Published: 2019
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26. Time, frequency and information domain analysis of heart period and QT variability in asymptomatic long QT syndrome type 2 patients.

Author: Vlasta Bari, Giulia Girardengo, Andrea Marchi, Beatrice De Maria, Paul A. Brink, Lia Crotti, Peter J. Schwartz, and Alberto Porta
Published: 2015
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27. Batch Action PoTential Analyser (BAPTA): an open source tool for automated high throughput analysis of cardiac action potentials

Author: Vladislav Leonov, Eleonora Torre, Carlotta Ronchi, Lia Crotti, Peter J Schwartz, Marcella Rocchetti, Antonio Zaza, and Luca Sala
Abstract: The cardiac action potential (AP) is a key species-specific feature of cardiomyocytes that occurs in response to coordinated actions of ion channels. It represents the first step of the cardiac excitation-contraction coupling and it is crucial for cardiomyocyte (CM) physiology. Changes in the cardiac AP may primarily occur as a consequence of diseases or as a direct or unwanted response to drugs. Our ability to quantify these changes defines the reliability of our measurements and its throughput.Cardiac AP parameters are often quantified through manual time-consuming data analysis protocols or custom-made and proprietary data analysis pipelines; to the best of our knowledge, no tools are currently available for automated cardiac AP analysis and AP parameter quantification.Here we introduce a free and open source software tool named Batch Action PoTential Analyser (BAPTA), written in the R language, designed to i) overcome the inherent operator-dependent bias on trace selection affecting reproducibility, ii) vastly improve the throughput of the analyses of large datasets and iii) analyse both spontaneous and triggered APs from CMs of multiple species and origin.We present here four use-cases in which BAPTA can be used at high throughput to investigate the effects of: 1) a disease (cardiomyopathy) on rat CMs, 2) drugs on mouse pacemaker cells, 3) rate-dependency of AP duration in guinea pig CMs and 4) metabolic electrophysiological maturation in human stem-cell-derived CMs. Overall, BAPTA consistently provides faster, more reproducible and scalable readouts which excellently correlate with manual analyses performed by experienced electrophysiologists.
Published: 2023
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28. Simple Forms: Legend, Saga, Myth, Riddle, Saying, Case, Memorabile, Fairytale, Joke

Author: André Jolles, Peter J. Schwartz
Published: 2017

29. Filtering approach based on empirical mode decomposition improves the assessment of short scale complexity in long QT syndrome type 1 population.

Author: Vlasta Bari, Andrea Marchi, Giulia Girardengo, Alfred L. George, Paul A. Brink, Sergio Cerutti, Lia Crotti, Peter J. Schwartz, and Alberto Porta
Published: 2014
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30. Cardiac sympathetic denervation in the prevention of genetically mediated life-threatening ventricular arrhythmias

Author: Peter J. Schwartz and Michael J. Ackerman
Subjects: Cardiology and Cardiovascular Medicine
Abstract: Proper management of patients affected by genetic disorders causing life-threatening arrhythmias is important for several reasons, including even societal ones, given the predominantly young age of those affected. Incorrect management often has dire consequences, ranging from unnecessary psychologic damage for the patients whose life becomes too limited by the fear of sudden death to equally avoidable tragedies when the entire armamentarium of effective therapies is not fully utilized. In this review, we focus primarily on long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) and deal specifically with the clinical impact of the most commonly used cardiac sympathetic denervation (CSD), namely left cardiac sympathetic denervation (LCSD). The two of us have used LCSD in the management of our patients with either LQTS or CPVT for a very long time and have been involved in ∼500 such interventions. It is on the basis of this personal and direct experience that we wish to share our views with clinical cardiologists and electrophysiologists, adult and paediatric, and with genetic cardiologists. We will begin by reviewing the history and rationale underlying sympathetic denervation therapy and will continue with a disease-specific intensification of therapy, and then with a discussion on how the impressive efficacy of LCSD should translate into guideline-directed therapy in both current and future guidelines, in order to upgrade the quality of care in the era of precision medicine.
Published: 2022
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31. Left Cardiac Sympathetic Denervation for Long QT Syndrome

Author: Cuilan Li, Lia Crotti, Veronica Dusi, Federica Dagradi, Gaetano M. De Ferrari, Roberto Rordorf, Maria Shkolnikova, Peter J. Schwartz, Carla Spazzolini, Attilio Odero, Luigi Pugliese, Silvia Castelletti, and Alessandro Vicentini
Subjects: medicine.medical_specialty, business.industry, Long QT syndrome, medicine.medical_treatment, First year of life, medicine.disease, Implantable cardioverter-defibrillator, QT interval, Asymptomatic, Sudden death, Sympathetic Denervation, Internal medicine, Cardiology, Medicine, Icd shocks, medicine.symptom, business
Abstract: Objectives This study sought to report our single-center experience with left cardiac sympathetic denervation (LCSD) for long QT syndrome (LQTS) since 1973. Background LCSD is still underutilized because clinicians are often uncertain whether to use it versus an implantable cardioverter-defibrillator (ICD). Methods We performed LCSD in 125 patients with LQTS (58% women, mean QT interval corrected for frequency [QTc] 527 ± 60 ms, 90% on beta blockers) with a follow-up of 12.9 ± 10.3 years. They were retrospectively divided into 4 groups according to the clinical/genetic status: very high risk (n = 18, symptomatic in the first year of life or with highly malignant genetics), with aborted cardiac arrest (ACA; n = 31), with syncope and/or ICD shocks on beta blockers (n = 45), in primary prevention (n = 31). Results After LCSD, 17% in the very high risk group remained asymptomatic, compared with 52%, 47%, and 97% in the other 3 groups (P Conclusions We provide definitive evidence for the long-term efficacy of LCSD in LQTS. The degree of antiarrhythmic protection is influenced by patient’s specificity and amount of QTc shortening. This novel approach to the analysis of the outcome allows cardiologists to rationally decide and tailor their management strategies to the individual features of their patients.
Published: 2022
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32. Harmonization of the definition of sudden cardiac death in longitudinal cohorts of the European Sudden Cardiac Arrest network – towards Prevention, Education, and New Effective Treatments (ESCAPE-NET) consortium

Author: Peder Emil Warming, Frederik Nybye Ågesen, Thomas Hadberg Lynge, Reza Jabbari, Robin L.A. Smits, Irene G.M. van Valkengoed, Sabrina J.G.C. Welten, Amber A. van der Heijden, Petra J. Elders, Marieke T. Blom, Xavier Jouven, Peter J. Schwartz, Christine M. Albert, Joline W. Beulens, Femke Rutters, Hanno L. Tan, Jean-Philippe Empana, Jacob Tfelt-Hansen, General practice, APH - Health Behaviors & Chronic Diseases, APH - Methodology, ACS - Diabetes & metabolism, Epidemiology and Data Science, ACS - Heart failure & arrhythmias, APH - Aging & Later Life, Graduate School, Public and occupational health, Cardiology, and APH - Societal Participation & Health
Subjects: 03 medical and health sciences, 0302 clinical medicine, Death, Sudden, Cardiac, Risk Factors, Cause of Death, Incidence, Humans, 030212 general & internal medicine, Longitudinal Studies, 030204 cardiovascular system & hematology, Cardiology and Cardiovascular Medicine, 3. Good health
Abstract: Background: The burden of sudden cardiac death (SCD) in the general population is substantial and SCD frequently occurs among people with few or no known risk factors for cardiac disease. Reported incidences of SCD vary due to differences in definitions and methodology between cohorts. This study aimed to develop a method for adjudicating SCD cases in research settings and to describe uniform case definitions of SCD in an international consortium harmonizing multiple longitudinal study cohorts. Methods: The harmonized SCD definitions include both case definitions using data from multiple sources (eg, autopsy reports, medical history, eyewitnesses) as well as a method using only information from registers (eg, cause of death registers, ICD-10 codes). Validation of the register-based method was done within the consortium using the multiple sources definition as gold standard and presenting sensitivity, specificity, accuracy and positive predictive value. Results: Consensus definitions of “definite,” “possible” and “probable” SCD for longitudinal study cohorts were reached. The definitions are based on a stratified approach to reflect the level of certainty of diagnosis and degree of information. The definitions can be applied to both multisource and register-based methods. Validation of the method using register-information in a cohort comprising 1335 cases yielded a sensitivity of 74%, specificity of 88%, accuracy of 86%, and positive predictive value of 54%. Conclusions: This study demonstrated that a harmonization of SCD classification across different methodological approaches is feasible. The developed classification can be used to study SCD in longitudinal cohorts and to merge cohorts with different levels of information.
Published: 2022
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33. Mutation location and I-Ks requlation in the arrhythmic risk of long QT syndrome type 1

Author: Carla Spazzolini, Isabelle Denjoy, Roel L.H.M.G. Spätjens, Peter J. Schwartz, Maria Christina Kotta, Paul A. Brink, Cristina Moreno, Kristina H. Haugaa, Sandrine R.M. Seyen, Maria Shkolnikova, Federica Dagradi, Lia Crotti, Marshall Heradien, Paul G.A. Volders, Silvia Castelletti, Matteo Pedrazzini, Schwartz, P, Moreno, C, Kotta, M, Pedrazzini, M, Crotti, L, Dagradi, F, Castelletti, S, Haugaa, K, Denjoy, I, Shkolnikova, M, Brink, P, Heradien, M, Seyen, S, Spatjens, R, Spazzolini, C, Volders, P, RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Cardiologie, and MUMC+: MA Med Staf Spec Cardiologie (9)
Subjects: medicine.medical_specialty, Long QT syndrome, Romano-Ward Syndrome, Mutation, Missense, Fast Track Clinical Research, REQUIREMENT, Stimulation, VARIANTS, medicine.disease_cause, PHENOTYPE, QT interval, Sudden cardiac death, MECHANISMS, chemistry.chemical_compound, Genetic, CHANNEL, Internal medicine, medicine, Clinical endpoint, Genetics, Missense mutation, Humans, Cyclic adenosine monophosphate, Mutation, business.industry, KVLQT1, medicine.disease, GENOTYPE, DOMINANT-NEGATIVE SUPPRESSION, chemistry, KCNQ1 Potassium Channel, Cardiology, GENETIC MODIFIER, Cardiology and Cardiovascular Medicine, business, LANGE-NIELSEN-SYNDROME
Abstract: Aims Mutation type, location, dominant-negative I Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I Ks stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. Methods and results Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.
Published: 2021
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34. 663 OCCURRENCE OF VENTRICULAR AND SUPRAVENTRICULAR ARRHYTHMIAS IN BRUGADA SYNDROME: RESULTS OF A TERTIARY REFERRAL CENTER EXPERIENCE

Author: Roberto Menè, Federica Dagradi, Fulvio Giovenzana, Francesco Maria Brasca, Giulia Girardengo, Gianfranco Parati, Giovanni Battista Perego, Lia Crotti, and Peter J Schwartz
Subjects: Cardiology and Cardiovascular Medicine
Abstract: Brugada Syndrome (BrS) is one of the most common channelopathies and is related to an increased risk of ventricular arrhythmias. Current guidelines recommend the implantation of a Cardiac Defibrillator (ICD) in those patients that have a diagnostic ECG pattern and a history of aborted cardiac arrest. Nevertheless, management of asymptomatic patients, who are the majority, remains controversial as their risk stratification is often based on the results of an inductive Electrophysiologic Study (EPS) the predictive accuracy of which is debated. Furthermore, BrS has also been associated to an increased risk of supraventricular tachy- and bradyarrhythmias. Aim to describe the occurrence of ventricular and supraventricular arrhythmias in BrS patients that receive an implantable cardiac monitoring device following an EPS study Methods we retrospectively identified all BrS patients followed at our tertiary referral centre that were candidate to an EPS. Patient were candidate to EPS if: (1) they had a spontaneous diagnostic Brugada pattern at ECG and (2) they had no history of previous ventricular arrhythmias or high-risk syncope. Those patients that tested positive for induction of a sustained ventricular arrhythmia at EPS received an ICD; those that tested negative received an ILR. During the follow-up visits, implantable devices were interrogated for the occurrence of ventricular and supraventricular arrhythmias. Results We identified 87 patients matching the inclusion criteria. Of these, 31 (35.7%) received an ICD for a positive EPS while the remaining 56 (64.3%) received an ILR. Over a mean follow-up period of 34 months (IQR 5-45, 249 patient-year), only one patient in the EPS positive group experienced a ventricular arrhythmia effectively treated by the ICD (0.3 events per patient-year) compared to zero patients in the EPS negative group (100% NPV, 3.2% PPV). Notably, implanted devices allowed for the detection of supraventricular arrhythmias in 12 out of the 87 patients (14%): 5 were cases of symptomatic sinus bradycardia, with an indication to permanent pacing in two of them, and 7 were cases of atrial tachycardia/fibrillation. Discussion in our registry, consistently with previous literature, ventricular arrhythmias in BrS patients are rare and a negative EPS identifies with high accuracy those that are at low risk for this event. Conversely, a positive EPS may overestimate the risk of these patients resulting, according to current practice, in frequent implantations of ICD that will never be required for defibrillation. Although the patient-year observation period of the presented cohort is sizeable, our results should be furtherly validated on multi-center cohorts with even longer follow-up periods. Nonetheless, our results support the idea that risk stratification tools other than EPS are probably needed to properly identify the minority of BrS patients that will experience a ventricular arrhythmia throughout their life. In addition, we report a considerable number of supraventricular arrhythmias recorded by the implanted cardiac monitoring devices in our population. This is consistent with the knowledge of BrS patients being at increased risk of sinoatrial node dysfunction and atrial fibrillation and may elicit a more widespread and methodical screening for these events.
Published: 2022
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35. Blocking nerves and saving lives: Left stellate ganglion block for electrical storms

Author: Simone Savastano and Peter J. Schwartz
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract: Patients who present with electrical storms (ES) due to rapid recurrence of ventricular tachycardia/ventricular fibrillation represent major medical emergencies without easy solutions. Antiarrhythmic drugs have limited value, and ES need to be stopped quickly to prevent irreversible patient deterioration and death. Since the mid-1970s, we have provided the rationale for interrupting cardiac sympathetic nerves and evidence of its antifibrillatory action in different clinical settings. Slowly but progressively, from isolated clinical reports to small case series, increasing evidence has indicated that pharmacologic stellate ganglion block (SGB) is highly effective in interrupting ES. However, medical guidelines have largely ignored SGB, and few centers are prepared to perform SGB in actual emergencies. Our own experience shows that a direct anatomic approach that does not require echocardiographic assistance can be performed rapidly, thus saving time in highly critical patients. In this review, we retrace the evolution in our understanding of the mechanism of action of SGB, discuss the current approaches and their limitations, and review the correct indications that overcome still existing biases. Furthermore, we propose a practical solution to increase the availability of SGB to more patients by extending the number of centers where this approach can be rapidly implemented.
Published: 2022

36. Resounding victory in golf of the Continental Europe Team of Cardiology

Author: Peter J Schwartz, Paolo Pantaleo, and Gian Paolo Bezante
Subjects: Europe, Cardiology, Humans, Golf, Cardiology and Cardiovascular Medicine, Cardiovascular System
Published: 2022
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37. An impedance-guided intra arterial catheter.

Author: Peter J. Schwartz, Cornie Scheffer, Pieter R. Fourie, and A. R. Coetzee
Published: 2013
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38. Refined multiscale entropy analysis of heart period and QT interval variabilities in long QT syndrome type-1 patients.

Author: Vlasta Bari, José F. Valencia, Montserrat Vallverdú, Giulia Girardengo, Tito Bassani, Andrea Marchi, Laura Calvillo, Pere Caminal, Sergio Cerutti, Paul A. Brink, Lia Crotti, Peter J. Schwartz, and Alberto Porta
Published: 2013
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39. Precision Medicine and cardiac channelopathies: when dreams meet reality

Author: Luca Sala, Peter J. Schwartz, Massimiliano Gnecchi, Gnecchi, M, Sala, L, and Schwartz, P
Subjects: Cardiac arrhythmias, Induced Pluripotent Stem Cells, Pluripotent stem cell, Arrhythmias, 030204 cardiovascular system & hematology, Cardiac arrhythmia, Medical care, Objective assessment, 03 medical and health sciences, 0302 clinical medicine, State of the Art Reviews, Pluripotent stem cells, Genetic, Genetics, Humans, Medicine, AcademicSubjects/MED00200, Precision Medicine, 030304 developmental biology, Cardiac channelopathies, 0303 health sciences, business.industry, Arrhythmias, Cardiac, Precision medicine, Cardiac channelopathie, 3. Good health, Clinical Practice, Editor's Choice, Death, Sudden, Cardiac, Risk analysis (engineering), Current practice, Risk stratification, Channelopathies, Long QT syndrome, Cardiology and Cardiovascular Medicine, business
Abstract: Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.
Published: 2021
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40. BASELINE AND CHANGE IN LIFE'S SIMPLE 7 CARDIOVASCULAR HEALTH SCORE AND RISK OF SUDDEN CARDIAC DEATH IN THE POPULATION

Author: Jean-Philippe Empana, Marie-Cécile PERIER, Peder Emil Warming, Eloi Marijon, Irene Van Valkengoed, Frederik Nybye Ågesen, Reza Jabbari, Eva Prescott, Rachel Climie, Peter J. Schwartz, Hanno L Tan, Jacob Tfelt-Hansen, and Xavier Jouven
Subjects: Cardiology and Cardiovascular Medicine
Published: 2023
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41. COVID-19 vaccination in patients with long QT syndrome

Author: Cheng-I. Wu, Peter J. Schwartz, Michael J. Ackerman, and Arthur A.M. Wilde
Subjects: SARS-CoV-2, COVID-19, Inherited cardiac arrhythmias, Long QT syndrome, Cardiology and Cardiovascular Medicine, Vaccinations
Abstract: Patients with long QT syndrome (LQTS) face potential threats from COVID-19 vaccination. Fever is one of the issues that is not uncommon after vaccination, and it usually takes place within two days. In particular, patients with type 2 LQTS based on trafficking-deficient variants are probably vulnerable to arrhythmogenicity under febrile conditions. Furthermore, myocarditis is one of the rare complications that is possibly associated with acquired QT prolongation and puts patients with LQTS at risk of life-threatening arrhythmia. Moreover, postural orthostatic tachycardia syndrome is another rare condition that, perhaps, poses LQTS patients susceptible to life-threatening arrhythmia when QT interval does not shorten optimally during tachycardia. In this review, we recommended prudent measurements to beneficially reduce the risk for patients with LQTS when vaccination or booster doses are eligible.
Published: 2022

42. Labour in a Single Shot: Critical Perspectives on Antje Ehmann and Harun Farocki’s Global Video Project

Author: Roy Grundmann, Peter J. Schwartz, Gregory H. Williams, Detlef Gericke, Antje Ehmann, Thomas Elsaesser, Dale Hudson, Patricia R. Zimmermann, José Gatti, David Barker, Jeannie Simms, Thomas Stubblefield, Gloria Sutton, Vinicius Navarro, Harun Farocki, Kok Korpershoek, Crius Group, Roy Grundmann, Peter J. Schwartz, Gregory H. Williams, Detlef Gericke, Antje Ehmann, Thomas Elsaesser, Dale Hudson, Patricia R. Zimmermann, José Gatti, David Barker, Jeannie Simms, Thomas Stubblefield, Gloria Sutton, Vinicius Navarro, Harun Farocki, Kok Korpershoek, and Crius Group
Abstract: This collection of essays offers a critical assessment of Labour in a Single Shot, a groundbreaking documentary video workshop. From 2011 to 2014, curator Antje Ehmann and film- and video-maker Harun Farocki produced an art project of truly global proportions. They travelled to fifteen cities around the world to conduct workshops inspired by cinema history’s first film, Workers Leaving the Lumière Factory, shot in 1895 by the Lumière brothers in France. While the workshop videos are in colour and the camera was not required to remain static, Ehmann and Farocki’s students were tasked with honouring the original Lumière film’s basic parameters ..., https://www.librarystack.org/labour-in-a-single-shot-critical-perspectives-on-antje-ehmann-and-harun-farockis-global-video-project/?ref=unknown
Published: 2022

43. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

Author: M Wilde, A, Semsarian, C, F Márquez, M, Sepehri Shamloo, A, J Ackerman, M, A Ashley, E, Sternick Eduardo, B, Barajas-Martinez, H, R Behr, E, R Bezzina, C, Breckpot, J, Charron, P, Chockalingam, P, Crotti, L, H Gollob, M, Lubitz, S, Makita, N, Ohno, S, Ortiz-Genga, M, Sacilotto, L, Schulze-Bahr, E, Shimizu, W, Sotoodehnia, N, Tadros, R, S Ware, J, S Winlaw, D, S Kaufman, E, Aiba, T, Bollmann, A, Choi, J, Dalal, A, Darrieux, F, Giudicessi, J, Guerchicoff, M, Hong, K, D Krahn, A, Mac Intyre, C, A Mackall, J, Mont, L, Napolitano, C, Ochoa Juan, P, Peichl, P, C Pereira, A, J Schwartz, P, Skinner, J, Stellbrink, C, Tfelt-Hansen, J, Deneke, T, Arthur A M Wilde, Christopher Semsarian, Manlio F Márquez, Alireza Sepehri Shamloo, Michael J Ackerman, Euan A Ashley, Back Sternick Eduardo, Héctor Barajas-Martinez, Elijah R Behr, Connie R Bezzina, Jeroen Breckpot, Philippe Charron, Priya Chockalingam, Lia Crotti, Michael H Gollob, Steven Lubitz, Naomasa Makita, Seiko Ohno, Martín Ortiz-Genga, Luciana Sacilotto, Eric Schulze-Bahr, Wataru Shimizu, Nona Sotoodehnia, Rafik Tadros, James S Ware, David S Winlaw, Elizabeth S Kaufman, Takeshi Aiba, Andreas Bollmann, Jong-Il Choi, Aarti Dalal, Francisco Darrieux, John Giudicessi, Mariana Guerchicoff, Kui Hong, Andrew D Krahn, Ciorsti Mac Intyre, Judith A Mackall, Lluís Mont, Carlo Napolitano, Pablo Ochoa Juan, Petr Peichl, Alexandre C Pereira, Peter J Schwartz, Jon Skinner, Christoph Stellbrink, Jacob Tfelt-Hansen, Thomas Deneke, M Wilde, A, Semsarian, C, F Márquez, M, Sepehri Shamloo, A, J Ackerman, M, A Ashley, E, Sternick Eduardo, B, Barajas-Martinez, H, R Behr, E, R Bezzina, C, Breckpot, J, Charron, P, Chockalingam, P, Crotti, L, H Gollob, M, Lubitz, S, Makita, N, Ohno, S, Ortiz-Genga, M, Sacilotto, L, Schulze-Bahr, E, Shimizu, W, Sotoodehnia, N, Tadros, R, S Ware, J, S Winlaw, D, S Kaufman, E, Aiba, T, Bollmann, A, Choi, J, Dalal, A, Darrieux, F, Giudicessi, J, Guerchicoff, M, Hong, K, D Krahn, A, Mac Intyre, C, A Mackall, J, Mont, L, Napolitano, C, Ochoa Juan, P, Peichl, P, C Pereira, A, J Schwartz, P, Skinner, J, Stellbrink, C, Tfelt-Hansen, J, Deneke, T, Arthur A M Wilde, Christopher Semsarian, Manlio F Márquez, Alireza Sepehri Shamloo, Michael J Ackerman, Euan A Ashley, Back Sternick Eduardo, Héctor Barajas-Martinez, Elijah R Behr, Connie R Bezzina, Jeroen Breckpot, Philippe Charron, Priya Chockalingam, Lia Crotti, Michael H Gollob, Steven Lubitz, Naomasa Makita, Seiko Ohno, Martín Ortiz-Genga, Luciana Sacilotto, Eric Schulze-Bahr, Wataru Shimizu, Nona Sotoodehnia, Rafik Tadros, James S Ware, David S Winlaw, Elizabeth S Kaufman, Takeshi Aiba, Andreas Bollmann, Jong-Il Choi, Aarti Dalal, Francisco Darrieux, John Giudicessi, Mariana Guerchicoff, Kui Hong, Andrew D Krahn, Ciorsti Mac Intyre, Judith A Mackall, Lluís Mont, Carlo Napolitano, Pablo Ochoa Juan, Petr Peichl, Alexandre C Pereira, Peter J Schwartz, Jon Skinner, Christoph Stellbrink, Jacob Tfelt-Hansen, and Thomas Deneke
Published: 2022

44. Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility (Nature Genetics, (2022), 54, 3, (232-239), 10.1038/s41588-021-01007-6)

Author: Julien Barc, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Julien Barc, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina
Abstract: In the version of this article initially published, Federico Manevy’s name appeared with a middle initial in error. The name has been corrected in the HTML and PDF versions of the article.
Published: 2022

45. Molecular genetic testing in athletes: Why and when a position statement from the Italian Society of Sports Cardiology

Author: Castelletti, S, Zorzi, A, Ballardini, E, Basso, C, Biffi, A, Brancati, F, Cavarretta, E, Crotti, L, Contursi, M, D'Aleo, A, D'Ascenzi, F, Delise, P, Dello Russo, A, Gazale, G, Mos, L, Novelli, V, Palamà, Z, Palermi, S, Palmieri, V, Patrizi, G, Pelliccia, A, Pilichou, K, Romano, S, Sarto, P, J Schwartz, P, Tiberi, M, Zeppilli, P, Corrado, D, Sciarra, L, Silvia Castelletti, Alessandro Zorzi, Enrico Ballardini, Cristina Basso, Alessandro Biffi, Francesco Brancati, Elena Cavarretta, Lia Crotti, Maurizio Contursi, Antonio D'Aleo, Flavio D'Ascenzi, Pietro Delise, Antonio Dello Russo, Giovanni Gazale, Lucio Mos, Valeria Novelli, Zefferino Palamà, Stefano Palermi, Vincenzo Palmieri, Giampiero Patrizi, Antonio Pelliccia, Kalliopi Pilichou, Silvio Romano, Patrizio Sarto, Peter J Schwartz, Monica Tiberi, Paolo Zeppilli, Domenico Corrado, Luigi Sciarra, Castelletti, S, Zorzi, A, Ballardini, E, Basso, C, Biffi, A, Brancati, F, Cavarretta, E, Crotti, L, Contursi, M, D'Aleo, A, D'Ascenzi, F, Delise, P, Dello Russo, A, Gazale, G, Mos, L, Novelli, V, Palamà, Z, Palermi, S, Palmieri, V, Patrizi, G, Pelliccia, A, Pilichou, K, Romano, S, Sarto, P, J Schwartz, P, Tiberi, M, Zeppilli, P, Corrado, D, Sciarra, L, Silvia Castelletti, Alessandro Zorzi, Enrico Ballardini, Cristina Basso, Alessandro Biffi, Francesco Brancati, Elena Cavarretta, Lia Crotti, Maurizio Contursi, Antonio D'Aleo, Flavio D'Ascenzi, Pietro Delise, Antonio Dello Russo, Giovanni Gazale, Lucio Mos, Valeria Novelli, Zefferino Palamà, Stefano Palermi, Vincenzo Palmieri, Giampiero Patrizi, Antonio Pelliccia, Kalliopi Pilichou, Silvio Romano, Patrizio Sarto, Peter J Schwartz, Monica Tiberi, Paolo Zeppilli, Domenico Corrado, and Luigi Sciarra
Abstract: Molecular genetic testing is an increasingly available test to support the clinical diagnosis of inherited cardiovascular diseases through identification of pathogenic gene variants and to make a preclinical genetic diagnosis among proband's family members (so-called “cascade family screening”). In athletes, the added value of molecular genetic testing is to assist in discriminating between physiological adaptive changes of the athlete's heart and inherited cardiovascular diseases, in the presence of overlapping phenotypic features such as ECG changes, imaging abnormalities or arrhythmias (“grey zone”). Additional benefits of molecular genetic testing in the athlete include the potential impact on the disease risk stratification and the implications for eligibility to competitive sports. This position statement of the Italian Society of Sports Cardiology aims to guide general sports medical physicians and sports cardiologists on clinical decision as why and when to perform a molecular genetic testing in the athlete, highlighting strengths and weaknesses for each inherited cardiovascular disease at-risk of sudden cardiac death during sport. The importance of early (preclinical) diagnosis to prevent the negative effects of exercise on phenotypic expression, disease progression and worsening of the arrhythmogenic substrate is also addressed.
Published: 2022

46. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author: Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina
Abstract: Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.
Published: 2022

47. Infanticide vs. inherited cardiac arrhythmias

Author: Vicki Athanasopoulos, Todor Arsov, Matthew C. Cook, Sui Rong Wayne Chen, Peter J. Schwartz, Ruiwu Wang, Deborah DiSilvestre, Hariharan Raju, David A Wallace, Richard Redon, Marcin Adamski, Helene Halkjær Jensen, Ivy E. Dick, Antony Kaspi, Melanie Bahlo, Matthew A. Field, Jinhong Wei, Lia Crotti, Michael Toft Overgaard, Mette Nyegaard, Haloom Rafehi, Bárbara B Ribeiro de Oliveira-Mendes, Carola G. Vinuesa, Yafei Zhang, Flavien Charpentier, Isabelle Baró, Malene Brohus, Aalborg University [Denmark] (AAU), Australian National University (ANU), Columbia University Irving Medical Center (CUIMC), Aarhus University [Aarhus], Istituto Auxologico Italiano, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Macquarie University [Sydney], University of Maryland School of Medicine, University of Maryland System, University of Calgary, The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Brohus, M, Arsov, T, Wallace, D, Jensen, H, Nyegaard, M, Crotti, L, Adamski, M, Zhang, Y, Field, M, Athanasopoulos, V, Baró, I, Ribeiro de Oliveira-Mendes, B, Redon, R, Charpentier, F, Raju, H, Disilvestre, D, Wei, J, Wang, R, Rafehi, H, Kaspi, A, Bahlo, M, Dick, I, Chen, S, Cook, M, Vinuesa, C, Overgaard, M, and Schwartz, P
Subjects: Tachycardia, MED/03 - GENETICA MEDICA, Infanticide, 030204 cardiovascular system & hematology, Ventricular tachycardia, Ryanodine receptor 2, Sudden cardiac death, ACTIVATION, BSN, Death, Sudden, 0302 clinical medicine, VENTRICULAR-TACHYCARDIA, AcademicSubjects/MED00200, CALMODULIN, Child, 0303 health sciences, High-Throughput Nucleotide Sequencing, Smothering, Sudden unexpected death, 3. Good health, Child, Preschool, Cardiology, Female, INACTIVATION, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Channelopathies and Cardiomyopathies, Long QT syndrome, Catecholaminergic polymorphic ventricular tachycardia, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Clinical Research, Physiology (medical), Internal medicine, BASSOON, medicine, Humans, 030304 developmental biology, MUTATIONS, business.industry, Calmodulinopathy, Australia, Infant, Cardiac arrhythmia, Arrhythmias, Cardiac, Ryanodine Receptor Calcium Release Channel, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Death, Sudden, Cardiac, Tachycardia, Ventricular, CALM2, business
Abstract: Aims In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children’s deaths as part of an inquiry into the mother’s convictions. Methods and results Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. Conclusion A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths., Graphical Abstract
Published: 2020
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48. Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk

Author: Dan Ye, Todd J. Herron, Ryan P. O'Connell, Michael J. Ackerman, Silvia Castelletti, Maria Christina Kotta, Charles Antzelevitch, Lia Crotti, Guadalupe Guerrero-Serna, Andre Monteiro da Rocha, Margherita Torchio, Hassan Hussein Musa, Justus M.B. Anumonwo, Michael A. Makara, Peter J. Mohler, Brad Rosinski, Cherisse A. Marcou, Vladislav V. Nesterenko, Michelle L. Milstein, David J. Tester, Federica Dagradi, Peter J. Schwartz, Musa, H, Marcou, C, Herron, T, Makara, M, Tester, D, O'Connell, R, Rosinski, B, Guerrero-Serna, G, Milstein, M, Monteiro Da Rocha, A, Ye, D, Crotti, L, Nesterenko, V, Castelletti, S, Torchio, M, Kotta, M, Dagradi, F, Antzelevitch, C, Mohler, P, Schwartz, P, Ackerman, M, and Anumonwo, J
Subjects: Scaffold protein, Physiology, Long QT syndrome, BIO/18 - GENETICA, Biology, arrhythmia, medicine.disease_cause, Afterdepolarization, Discs Large Homolog 1 Protein, Mice, BIO/09 - FISIOLOGIA, Physiology (medical), medicine, Animals, Humans, Myocytes, Cardiac, Sap97, Ion channel, Brugada syndrome, Mice, Knockout, Mutation, Myocardium, Arrhythmias, Cardiac, Heart, Cardiac action potential, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Cell biology, ion channel, DLG1, biology.protein, Cardiology and Cardiovascular Medicine, Research Article
Abstract: Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 (DLG1) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current (I(to)) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease. NEW & NOTEWORTHY The gene encoding SAP97 (DLG1) joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97’s candidacy as a minor Brugada syndrome susceptibility gene.
Published: 2020
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49. MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes

Author: Eleonora Torre, Peter J. Schwartz, Lia Crotti, Yee-Ki Lee, Matteo Pedrazzini, Pak C. Sham, Massimiliano Gnecchi, Xinru Ran, Hung-Fat Tse, Manuela Mura, Timothy Shin Heng Mak, Marcella Rocchetti, Luca Sala, Antonio Zaza, Lee, Y, Sala, L, Mura, M, Rocchetti, M, Pedrazzini, M, Ran, X, Mak, T, Crotti, L, Sham, P, Torre, E, Zaza, A, Schwartz, P, Tse, H, and Gnecchi, M
Subjects: Physiology, Nedd4 Ubiquitin Protein Ligases, Arrhythmias, 030204 cardiovascular system & hematology, medicine.disease_cause, Electrocardiography, 0302 clinical medicine, BIO/09 - FISIOLOGIA, AcademicSubjects/MED00200, Myocytes, Cardiac, KvLQT1, Variant, Cells, Cultured, Exome sequencing, Genetics, 0303 health sciences, Mutation, biology, Variants, Protein Tyrosine Phosphatases, Non-Receptor, Phenotype, 3. Good health, KCNQ1 Potassium Channel, Long QT syndrome, Cardiology and Cardiovascular Medicine, Arrhythmia, Induced Pluripotent Stem Cells, hERG, Protein degradation, Polymorphism, Single Nucleotide, Cardiac Electrophysiology and Arrhythmia, 03 medical and health sciences, Physiology (medical), Nedd4L, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, NEDD4L, Genes, Modifier, business.industry, Induced pluripotent stem cell, Original Articles, medicine.disease, MTMR4, Proteolysis, biology.protein, business
Abstract: Aims In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action. Methods and results We generated human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from two patients carrying the same KCNQ1-Y111C mutation, but presenting opposite clinical phenotypes. We showed that the phenotype of the iPSC-CMs derived from the symptomatic patient is due to impaired trafficking and increased degradation of the mutant KCNQ1 and wild-type human ether-a-go-go-related gene. In the iPSC-CMs of the asymptomatic (AS) patient, the activity of an E3 ubiquitin-protein ligase (Nedd4L) involved in channel protein degradation was reduced and resulted in a decreased arrhythmogenic substrate. Two single-nucleotide variants (SNVs) on the Myotubularin-related protein 4 (MTMR4) gene, an interactor of Nedd4L, were identified by whole-exome sequencing as potential contributors to decreased Nedd4L activity. Correction of these SNVs by CRISPR/Cas9 unmasked the LQTS phenotype in AS cells. Importantly, the same MTMR4 variants were present in 77% of AS Y111C mutation carriers of a separate cohort. Thus, genetically mediated interference with Nedd4L activation seems associated with protective effects. Conclusion Our finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS. It provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.
Published: 2020
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50. Continued misuse of orphan drug legislation: a life-threatening risk for mexiletine

Author: Ellen 't Hoen, Stefan Kääb, Peter J. Schwartz, Wilbert J Bannenberg, Antoine Leenhardt, Josep Brugada, Pier D. Lambiase, Carla E. M. Hollak, Vincent Probst, Bernard Belhassen, Jacob Tfelt-Hansen, Ruben Casado-Arroyo, Bas C. Stunnenberg, Pieter G. Postema, Arthur A.M. Wilde, Baziel G.M. van Engelen, A. John Camm, Pedro Brugada, Silvia G. Priori, Christian Veltmann, Sami Viskin, Elena Arbelo, Elijah R. Behr, Clinical sciences, Heartrhythmmanagement, Cardio-vascular diseases, and Faculty of Medicine and Pharmacy
Subjects: Medicine(all), medicine.medical_specialty, business.industry, MEDLINE, Mexiletine, Legislation, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Legislation, Drug, Orphan drug, Misuse of Orphan Drug Legislation, life-threatening, medicine, Humans, Cardiology and Cardiovascular Medicine, Intensive care medicine, business, risk, medicine.drug
Abstract: Contains fulltext : 218857.pdf (Publisher’s version ) (Closed access)
Published: 2020
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