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  1. Article ; Online: Rare Diseases Inform Myocardial Phenotypes for Precision Medicine.

    Macrae, Calum A

    Journal of cardiac failure

    2018  Volume 24, Issue 10, Page(s) 680–681

    MeSH term(s) Cardiomyopathies ; Child ; Friedreich Ataxia ; Heart Failure ; Humans ; Phenotype ; Precision Medicine ; Rare Diseases
    Language English
    Publishing date 2018-09-13
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 1281194-4
    ISSN 1532-8414 ; 1071-9164
    ISSN (online) 1532-8414
    ISSN 1071-9164
    DOI 10.1016/j.cardfail.2018.09.005
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  2. Article: Discovering New Diseases to Accelerate Precision Medicine.

    Macrae, Calum A

    Transactions of the American Clinical and Climatological Association

    2017  Volume 128, Page(s) 83–89

    Abstract: A rate-limiting step in multiple areas of medicine is the limited number of discrete disorders that current technologies are able to identify. Most clinical disease entities are aggregates of large numbers of discrete biological processes that simply ... ...

    Abstract A rate-limiting step in multiple areas of medicine is the limited number of discrete disorders that current technologies are able to identify. Most clinical disease entities are aggregates of large numbers of discrete biological processes that simply happen to share one or two common features. We have begun to translate a wide range of new technologies to the clinic in an effort to improve the resolution and the efficiency of bedside diagnostics with a view to improving drug trials, genetic studies, and the effectiveness of the clinician in a digital environment. The general trajectory for change that new technologies will bring is outlined with some specific examples of areas where such change has already begun to occur.
    Language English
    Publishing date 2017
    Publishing country United States
    Document type Journal Article
    ZDB-ID 603823-2
    ISSN 0065-7778
    ISSN 0065-7778
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery.

    Macrae, Calum A

    Expert opinion on drug discovery

    2010  Volume 5, Issue 7, Page(s) 619–632

    Abstract: IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information ...

    Abstract IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease biology, but emphasizes the importance of the rigor of the disease model.
    Language English
    Publishing date 2010-08-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2259618-5
    ISSN 1746-045X ; 1746-0441
    ISSN (online) 1746-045X
    ISSN 1746-0441
    DOI 10.1517/17460441.2010.492826
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Genetic testing in cardiovascular diseases.

    Arndt, Anne-Karin / Macrae, Calum A

    Current opinion in cardiology

    2014  

    Abstract: Purpose of review: The review is designed to outline the major developments in genetic testing in the cardiovascular arena in the past year or so. This is an exciting time in genetic testing as whole exome and whole genome approaches finally reach the ... ...

    Abstract Purpose of review: The review is designed to outline the major developments in genetic testing in the cardiovascular arena in the past year or so. This is an exciting time in genetic testing as whole exome and whole genome approaches finally reach the clinic. These new approaches offer insight into disease causation in families in which this might previously have been inaccessible, and also bring a wide range of interpretative challenges.
    Recent findings: Among the most significant recent findings has been the extent of physiologic rare coding variation in the human genome. New disease genes have been identified through whole exome studies in neonatal arrhythmia, congenital heart disease and coronary artery disease that were simply inaccessible with other techniques. This has not only shed light on the challenges of genetic testing at this scale, but has also sharply defined the limits of prior gene-panel focused testing. As novel therapies targeting specific genetic subsets of disease become available, genetic testing will become a part of routine clinical care.
    Summary: The pace of change in sequencing technologies has begun to transform clinical medicine, and cardiovascular disease is no exception. The complexity of such studies emphasizes the importance of real-time communication between the genetics laboratory and genetically informed clinicians. New efforts in data and knowledge management will be central to the continued advancement of genetic testing.
    Language English
    Publishing date 2014-03-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645186-x
    ISSN 1531-7080 ; 0268-4705
    ISSN (online) 1531-7080
    ISSN 0268-4705
    DOI 10.1097/HCO.0000000000000056
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  5. Article ; Online: Long QT syndrome.

    Abrams, Dominic J / Macrae, Calum A

    Circulation

    2014  Volume 129, Issue 14, Page(s) 1524–1529

    MeSH term(s) Adult ; Dose-Response Relationship, Drug ; ERG1 Potassium Channel ; Electrocardiography ; Ether-A-Go-Go Potassium Channels/genetics ; Female ; Genetic Testing ; Humans ; Long QT Syndrome/diagnosis ; Long QT Syndrome/drug therapy ; Long QT Syndrome/genetics ; Mutation, Missense/genetics ; Nadolol/therapeutic use ; Treatment Outcome
    Chemical Substances ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; Nadolol (42200-33-9)
    Language English
    Publishing date 2014-04-08
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 80099-5
    ISSN 1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
    ISSN (online) 1524-4539
    ISSN 0009-7322 ; 0069-4193 ; 0065-8499
    DOI 10.1161/CIRCULATIONAHA.113.003985
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: The developmental basis of adult arrhythmia: atrial fibrillation as a paradigm.

    Kapur, Sunil / Macrae, Calum A

    Frontiers in physiology

    2013  Volume 4, Page(s) 221

    Abstract: Normal cardiac rhythm is one of the most fundamental physiologic phenomena, emerging early in the establishment of the vertebrate body plan. The developmental pathways underlying the patterning and maintenance of stable cardiac electrophysiology must be ... ...

    Abstract Normal cardiac rhythm is one of the most fundamental physiologic phenomena, emerging early in the establishment of the vertebrate body plan. The developmental pathways underlying the patterning and maintenance of stable cardiac electrophysiology must be extremely robust, but are only now beginning to be unraveled. The step-wise emergence of automaticity, AV delay and sequential conduction are each tightly regulated and perturbations of these patterning events is now known to play an integral role in pediatric and adult cardiac arrhythmias. Electrophysiologic patterning within individual cardiac chambers is subject to exquisite control and is influenced by early physiology superimposed on the underlying gene networks that regulate cardiogenesis. As additional cell populations migrate to the developing heart these too bring further complexity to the organ, as it adapts to the dynamic requirements of a growing organism. A comprehensive understanding of the developmental basis of normal rhythm will inform not only the mechanisms of inherited arrhythmias, but also the differential regional propensities of the adult heart to acquired arrhythmias. In this review we use atrial fibrillation as a generalizable example where the various factors are perhaps best understood.
    Language English
    Publishing date 2013-09-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2013.00221
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  7. Article: Changing the Scale and Efficiency of Chemical Warfare Countermeasure Discovery Using the Zebrafish.

    Peterson, Randall T / Macrae, Calum A

    Drug discovery today. Disease models

    2013  Volume 10, Issue 1

    Abstract: As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the ... ...

    Abstract As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approach that has been pioneered in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the establishment of a zebrafish platform for countermeasure discovery would offer a rapid response system for the development of antidotes to the continuous stream of new potential chemical warfare agents.
    Language English
    Publishing date 2013-11-05
    Publishing country Netherlands
    Document type Journal Article
    ISSN 1740-6757
    ISSN 1740-6757
    DOI 10.1016/j.ddmod.2013.05.001
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  8. Article ; Online: Revisiting risk stratification in hypertrophic cardiomyopathy: do we need to start from scratch?

    Lee, Ming-Sum / Macrae, Calum A

    Heart rhythm

    2012  Volume 9, Issue 1, Page(s) 64–65

    MeSH term(s) Cardiomyopathy, Hypertrophic/genetics ; Death, Sudden, Cardiac/etiology ; Female ; Humans ; Male ; Sarcomeres/genetics
    Language English
    Publishing date 2012-01
    Publishing country United States
    Document type Comment ; Editorial
    ZDB-ID 2229357-7
    ISSN 1556-3871 ; 1547-5271
    ISSN (online) 1556-3871
    ISSN 1547-5271
    DOI 10.1016/j.hrthm.2011.10.023
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  9. Article ; Online: Systematic approaches to toxicology in the zebrafish.

    Peterson, Randall T / Macrae, Calum A

    Annual review of pharmacology and toxicology

    2012  Volume 52, Page(s) 433–453

    Abstract: As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in ... ...

    Abstract As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology.
    MeSH term(s) Animals ; Carcinogenicity Tests ; Drug Delivery Systems ; Drug Design ; Drug Discovery ; Drug Evaluation, Preclinical/methods ; Gastrointestinal Tract/drug effects ; Heart/drug effects ; Liver/drug effects ; Models, Animal ; Muscles/drug effects ; Neurons/drug effects ; Pharmaceutical Preparations ; Pharmacokinetics ; Phenotype ; Toxicity Tests ; Zebrafish
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2012
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 196587-6
    ISSN 1545-4304 ; 0362-1642
    ISSN (online) 1545-4304
    ISSN 0362-1642
    DOI 10.1146/annurev-pharmtox-010611-134751
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  10. Article ; Online: Mutations in desmosomal protein genes and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.

    Saffitz, Jeffrey E / Macrae, Calum A

    Heart rhythm

    2010  Volume 7, Issue 1, Page(s) 30–32

    MeSH term(s) Arrhythmogenic Right Ventricular Dysplasia/genetics ; Desmosomes/genetics ; Humans ; Mutation
    Language English
    Publishing date 2010-01
    Publishing country United States
    Document type Comment ; Editorial
    ZDB-ID 2229357-7
    ISSN 1556-3871 ; 1547-5271
    ISSN (online) 1556-3871
    ISSN 1547-5271
    DOI 10.1016/j.hrthm.2009.10.028
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