The genetics underlying acquired long QT syndrome: impact for genetic screening

Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Véronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J.; Horie, Minoru

doi:10.1093/eurheartj/ehv695

Cited by 168 publications

(159 citation statements)

References 29 publications

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“…In addition, hiPSC‐CMs are also being used as model systems to test the effect of both known and novel drugs on cardiac channelopathies (Matsa et al , 2011; Zhang et al , 2012; Bellin et al , 2013; Di Pasquale et al , 2013; Zhang et al , 2014), with suppression of pathological pro‐arrhythmic potential and restoration of altered AP duration (APD) being two main endpoints. Clinical evidence has shown that pharmacological treatments can be of more benefit when properly calibrated in a disease‐specific or even mutation‐specific manner (Nebert and Vesell, 2006; Cavallari, 2012; Amin and Wilde, 2016; Itoh et al , 2016; Martiniano et al , 2016). This has been particularly evident for monogenic diseases targeting the cardiac electrical system (Priori, 1998; Tan et al , 2006), because genetic modifiers critically determine the clinical phenotype (Duchatelet et al , 2013; de Villiers et al , 2014).…”

Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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“…Candidate gene screening studies have been performed to explain diLQTS in large cohorts of patients as a form frustre of congenital LQTS. However, the prevalence of common mutations in the known LQTS genes was limited (from 10 to maximum 30%) [31][32][33][34]. As exemplified in our study, many subjects developing profound changes in cardiac repolarization in response to a pharmacological challenge do not present with clinical or electrocardiographic abnormalities at baseline, nor have familial history of syncope or sudden death [31][32][33][34].…”

Section: Discussionmentioning

confidence: 61%

“…However, the prevalence of common mutations in the known LQTS genes was limited (from 10 to maximum 30%) [31][32][33][34]. As exemplified in our study, many subjects developing profound changes in cardiac repolarization in response to a pharmacological challenge do not present with clinical or electrocardiographic abnormalities at baseline, nor have familial history of syncope or sudden death [31][32][33][34]. In a recent study with a Danish population cohort of 7000 subjects, Ghouse et al found that 26 congenital LQTS-associated variants (mainly affecting ion channels) did not influence QTc interval duration, syncopes or overall mortality [35].…”

Section: Discussionmentioning

confidence: 99%

Genome wide analysis of sotalol-induced IKr inhibition during ventricular repolarization, “GENEREPOL study”: lack of common variants with large effect sizes

Salem¹,

Germain²,

Hulot³

et al. 2017

Archives of Cardiovascular Diseases Supplements

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“…In the absence of references, novel variants were included when they were deemed to be pathogenic or likely pathogenic by applying the recently published ACMG guidelines, 18 which are based on criteria using typical types of variant evidence, including the frequencies in the population data and computational (in silico) predictive programs. 19 …”

Section: Clinical Course During the Follow-upmentioning

confidence: 99%

Mid-Term Follow-up of School-Aged Children With Borderline Long QT Interval

Miyazaki

Sakaguchi

Matsumura

et al. 2017

Circ J

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Background: There are no definitive diagnostic criteria or follow-up strategies for long QT syndrome (LQTS) in children with a borderline long QT interval (b-LQT). Methods and Results:We retrospectively evaluated the clinical course, genetic testing results, corrected QT interval (QTc), and LQTS score of 59 school-aged children (5-18 years old) with a b-LQT (400≤QTc<500 ms). Syncope, but neither aborted cardiac arrest nor sudden cardiac death, occurred in 2 patients during the follow-up (6±3.4 years) with LQTS scores ≥4.5 points. The genetic testing results were positive in 92%, 57%, and 67% of patients with high, intermediate, and low probabilities of LQTS, respectively. The maximum and mean QTc during the follow-up significantly differed among the categories with a probability of LQTS, but not the minimum QTc. However, the QTc at rest and at the recovery point after exercise stress testing dramatically changed at the last followup. Consequently, the probability of LQTS changed in half of the patients. Conclusions:The LQTS score is a reasonable indicator for evaluating school-aged children with a b-LQT, and patients with a low LQTS score appear to be at low risk for cardiac events. However, the LQTS score can change during follow-up. Therefore, when there is doubt or concern for patients with a b-LQT, it is preferable to continue following them. Guidelines on follow-up strategies are desired for b-LQT.

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The genetics underlying acquired long QT syndrome: impact for genetic screening

Cited by 168 publications

References 29 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Genome wide analysis of sotalol-induced IKr inhibition during ventricular repolarization, “GENEREPOL study”: lack of common variants with large effect sizes

Mid-Term Follow-up of School-Aged Children With Borderline Long QT Interval

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