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      Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells

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          Abstract

          A large number of drugs can induce prolongation of cardiac repolarization and life-threatening cardiac arrhythmias. The prediction of this side effect is however challenging as it usually develops in some genetically predisposed individuals with normal cardiac repolarization at baseline. Here, we describe a platform based on a genetically diverse panel of induced pluripotent stem cells (iPSCs) that reproduces susceptibility to develop a cardiotoxic drug response. We generated iPSC-derived cardiomyocytes from patients presenting in vivo with extremely low or high changes in cardiac repolarization in response to a pharmacological challenge with sotalol. In vitro, the responses to sotalol were highly variable but strongly correlated to the inter-individual differences observed in vivo. Transcriptomic profiling identified dysregulation of genes ( DLG2, KCNE4, PTRF, HTR2C, CAMKV) involved in downstream regulation of cardiac repolarization machinery as underlying high sensitivity to sotalol. Our findings offer novel insights for the development of iPSC-based screening assays for testing individual drug reactions.

          DOI: http://dx.doi.org/10.7554/eLife.19406.001

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          Common medications can disturb the electrical signals that cause the heart to beat, potentially resulting in sudden death. Many of the drugs that have these “cardiotoxic” effects were not designed to affect the heart, and include anti-allergenics and anti-vomiting drugs. In general, only a small proportion of individuals treated with these drugs will be at risk of fatal side effects; this risk variation is thought to be due to genetic differences. If these people could be reliably identified, the drugs could be used to treat others who will not develop cardiotoxic reactions, but it is difficult to predict the effect a drug will have on the beating of the heart.

          Stillitano, Hansen et al. have now investigated whether skin cells can be used to predict an individual’s likelihood of developing cardiotoxic side effects. Skin cells can be reprogrammed to form pluripotent stem cells, which have the ability to develop into any of the cell types in the adult body – including heart muscle cells. The effects of drugs could then be tested on these artificially created heart cells, yet it is not clear whether these effects would be the same as those seen in actual heart cells

          Stillitano, Hansen et al. created heart cells from skin samples collected from many different people and treated the cells with a drug that affects the rhythm of the heart. Some of the cells came from people whose heart rhythm is strongly affected by the drug, and others came from people whose heart rhythm is barely altered. The response of the lab-grown cells was closely related to whether the cells came from a person who was susceptible to the effects of the drug. Further investigation revealed that the genes that are important for maintaining a regular heartbeat differ in people who experience strong cardiotoxic side effects from those that do not.

          Overall, the results presented by Stillitano, Hansen et al. support the idea that induced pluripotent stem cells could be used to predict an individual’s risk of developing cardiotoxic reactions. Further work is now needed to develop this approach.

          DOI: http://dx.doi.org/10.7554/eLife.19406.002

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          Most cited references40

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          National surveillance of emergency department visits for outpatient adverse drug events.

          Adverse drug events are common and often preventable causes of medical injuries. However, timely, nationally representative information on outpatient adverse drug events is limited. To describe the frequency and characteristics of adverse drug events that lead to emergency department visits in the United States. Active surveillance from January 1, 2004, through December 31, 2005, through the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project. National estimates of the numbers, population rates, and severity (measured by hospitalization) of individuals with adverse drug events treated in emergency departments. Over the 2-year study period, 21,298 adverse drug event cases were reported, producing weighted annual estimates of 701,547 individuals (95% confidence interval [CI], 509,642-893,452) or 2.4 individuals per 1000 population (95% CI, 1.7-3.0) treated in emergency departments. Of these cases, 3487 individuals required hospitalization (annual estimate, 117,318 [16.7%]; 95% CI, 13.1%-20.3%). Adverse drug events accounted for 2.5% (95% CI, 2.0%-3.1%) of estimated emergency department visits for all unintentional injuries and 6.7% (95% CI, 4.7%-8.7%) of those leading to hospitalization and accounted for 0.6% of estimated emergency department visits for all causes. Individuals aged 65 years or older were more likely than younger individuals to sustain adverse drug events (annual estimate, 4.9 vs 2.0 per 1000; rate ratio [RR], 2.4; 95% CI, 1.8-3.0) and more likely to require hospitalization (annual estimate, 1.6 vs 0.23 per 1000; RR, 6.8; 95% CI, 4.3-9.2). Drugs for which regular outpatient monitoring is used to prevent acute toxicity accounted for 41.5% of estimated hospitalizations overall (1381 cases; 95% CI, 30.9%-52.1%) and 54.4% of estimated hospitalizations among individuals aged 65 years or older (829 cases; 95% CI, 45.0%-63.7%). Adverse drug events among outpatients that lead to emergency department visits are an important cause of morbidity in the United States, particularly among individuals aged 65 years or older. Ongoing, population-based surveillance can help monitor these events and target prevention strategies.
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            RNA-seq: technical variability and sampling

            Background RNA-seq is revolutionizing the way we study transcriptomes. mRNA can be surveyed without prior knowledge of gene transcripts. Alternative splicing of transcript isoforms and the identification of previously unknown exons are being reported. Initial reports of differences in exon usage, and splicing between samples as well as quantitative differences among samples are beginning to surface. Biological variation has been reported to be larger than technical variation. In addition, technical variation has been reported to be in line with expectations due to random sampling. However, strategies for dealing with technical variation will differ depending on the magnitude. The size of technical variance, and the role of sampling are examined in this manuscript. Results In this study three independent Solexa/Illumina experiments containing technical replicates are analyzed. When coverage is low, large disagreements between technical replicates are apparent. Exon detection between technical replicates is highly variable when the coverage is less than 5 reads per nucleotide and estimates of gene expression are more likely to disagree when coverage is low. Although large disagreements in the estimates of expression are observed at all levels of coverage. Conclusions Technical variability is too high to ignore. Technical variability results in inconsistent detection of exons at low levels of coverage. Further, the estimate of the relative abundance of a transcript can substantially disagree, even when coverage levels are high. This may be due to the low sampling fraction and if so, it will persist as an issue needing to be addressed in experimental design even as the next wave of technology produces larger numbers of reads. We provide practical recommendations for dealing with the technical variability, without dramatic cost increases.
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              Drug-induced long QT syndrome.

              The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current I(Kr), has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described.
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                Author and article information

                Contributors
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                30 January 2017
                2017
                : 6
                : e19406
                Affiliations
                [1 ]deptCardiovascular Research Center , Icahn School of Medicine at Mount Sinai , New York, United States
                [2 ]deptDepartment of Pharmacology and Systems Therapeutics, Systems Biology Center , Icahn School of Medicine at Mount Sinai , New York, United States
                [3 ]Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition , Paris, France
                [4 ]deptDepartment of Genetics and Genomic Sciences , Icahn School of Medicine at Mount Sinai , New York, United States
                [5 ]Cellectis Stem Cells , Paris, France
                [6]Hospital for Sick Children , Canada
                [7]Hospital for Sick Children , Canada
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-5463-6117
                Article
                19406
                10.7554/eLife.19406
                5279943
                28134617
                33621d89-759e-47bf-9231-4c4a8a2ac6ce
                © 2017, Stillitano et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 05 July 2016
                : 08 December 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P50 GM071558
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM54508
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: U54 HG008098
                Award Recipient :
                Funded by: Cellectis Company;
                Award ID: Research subvention
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Human Biology and Medicine
                Custom metadata
                2.5
                A genetically diverse panel of subject-specific induced pluripotent stem cells models the in vitro susceptibility of cardiac cells to develop a cardiotoxic drug response.

                Life sciences
                induced pluripotent stem cells,cardiotoxicity,arrhythmia,human
                Life sciences
                induced pluripotent stem cells, cardiotoxicity, arrhythmia, human

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