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      Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century

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          Abstract

          Risk stratification in the context of sudden cardiac death has been acknowledged as one of the major challenges facing cardiology for the past four decades. In recent years, the advent of high performance computing has facilitated organ‐level simulation of the heart, meaning we can now examine the causes, mechanisms and impact of cardiac dysfunction in silico. As a result, computational cardiology, largely driven by the Physiome project, now stands at the threshold of clinical utility in regards to risk stratification and treatment of patients at risk of sudden cardiac death. In this white paper, we outline a roadmap of what needs to be done to make this translational step, using the relatively well‐developed case of acquired or drug‐induced long QT syndrome as an exemplar case.

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          Patient-specific induced pluripotent stem cell derived models of LEOPARD syndrome

          Generation of reprogrammed induced pluripotent stem cells (iPSC) from patients with defined genetic disorders promises important avenues to understand the etiologies of complex diseases, and the development of novel therapeutic interventions. We have generated iPSC from patients with LEOPARD syndrome (LS; acronym of its main features: Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary valve stenosis, Abnormal genitalia, Retardation of growth and Deafness), an autosomal dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-MAPK signaling diseases, which also includes Noonan syndrome (NS), with pleiomorphic effects on several tissues and organ systems1,2. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSC have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LS-iPSC are larger, have a higher degree of sarcomeric organization and preferential localization of NFATc4 in the nucleus when compared to cardiomyocytes derived from human embryonic stem cells (HESC) or wild type (wt) iPSC derived from a healthy brother of one of the LS patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signaling pathways that may promote the disease phenotype.
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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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              Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic.

              Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class 2I), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). The cardiac electrophysiological effects of 702 chemicals (class 2I or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by >50 ms, with induction of instability, triangulation, and reverse use-dependence (n=59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (n=19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (P<0.001). Shortening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes). Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.
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                Author and article information

                Contributors
                a.hill@victorchang.edu.au
                Journal
                J Physiol
                J. Physiol. (Lond.)
                10.1111/(ISSN)1469-7793
                TJP
                jphysiol
                The Journal of Physiology
                John Wiley and Sons Inc. (Hoboken )
                0022-3751
                1469-7793
                09 June 2016
                01 December 2016
                09 June 2016
                : 594
                : 23 ( doiID: 10.1113/tjp.2016.594.issue-23 )
                : 6893-6908
                Affiliations
                [ 1 ]Victor Chang Cardiac Research Institute 405 Liverpool Street Darlinghurst NSW 2010Australia
                [ 2 ] St. Vincent's Clinical SchoolUniversity of New South Wales Sydney NSW 2052Australia
                [ 3 ]AnaBios Corporation 3030 Bunker Hill St. San Diego CA 92109USA
                [ 4 ]University of Rochester Medical Center Rochester NY 14642USA
                [ 5 ] Global Safety PharmacologyPfizer Inc MS8274‐1347 Eastern Point Road Groton CT 06340USA
                [ 6 ] School of Physiology, Pharmacology and NeuroscienceUniversity of Bristol BristolUK
                [ 7 ]Vanderbilt University School of Medicine 1285 Medical Research Building IV Nashville Tennessee 37232USA
                [ 8 ] Computational Biology, Department of Computer ScienceUniversity of Oxford OxfordUnited Kingdom
                [ 9 ] Cardiac Inherited Disease GroupStarship Hospital AucklandNew Zealand
                Author notes
                [*] [* ] Corresponding author A. P. Hill: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, 405, Liverpool Street, Darlinghurst, NSW 2010, Australia. Email: a.hill@ 123456victorchang.edu.au
                Article
                TJP7261
                10.1113/JP272015
                5134408
                27060987
                d5d14156-29b9-4568-9263-69fe2c2b5011
                © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, Tables: 0, Pages: 16, Words: 13144
                Product
                Funding
                Funded by: Australian Research Council
                Award ID: FT110100075
                Funded by: National Health and Medical Research Council
                Award ID: 1019693
                Funded by: Wellcome Trust/Royal Society
                Award ID: 101222/Z/13/Z
                Categories
                Computational Physiology and Modelling
                Cardiovascular Physiology
                Cardiovascular Conditions, Disorders and Treatments
                White Paper
                Special section reviews: The Cardiac Physiome Project
                Custom metadata
                2.0
                tjp7261
                1 December 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:01.12.2016

                Human biology

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