Cardiac tissue slices with prolonged survival for in vitro drug safety screening

Bussek, Alexandra; Schmidt, Matthias; Bauriedl, Jessica; Ravens, Ursula; Wettwer, Erich; Lohmann, Horst

doi:10.1016/j.vascn.2011.12.002

Cited by 27 publications

(22 citation statements)

References 38 publications

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“…As myocardial slices provide a clinically relevant and representative human model system in vitro they are particularly useful for translational studies (7). A substantial amount of work has demonstrated that myocardial slices can be used for pharmacological testing and in vitro drug safety screening (6,7,13,14,22). They have also been used to study the integrative capacity of a number of cell types as part of the development of cell-replacement strategies (16,26,27).…”

Section: Development and Applicationsmentioning

confidence: 99%

Preparation of viable adult ventricular myocardial slices from large and small mammals

et al. 2017

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This protocol describes the preparation of highly viable adult ventricular myocardial slices from the hearts of small and large mammals, including rodents, pigs, dogs and humans. Adult ventricular myocardial slices are 100- to 400-μm-thick slices of living myocardium that retain the native multicellularity, architecture and physiology of the heart. This protocol provides a list of the equipment and reagents required alongside a detailed description of the methodology for heart explantation, tissue preparation, slicing with a vibratome and handling of myocardial slices. Supplementary videos are included to visually demonstrate these steps. A number of critical steps are addressed that must be followed in order to prepare highly viable myocardial slices. These include identification of myocardial fiber direction and fiber alignment within the tissue block, careful temperature control, use of an excitation-contraction uncoupler, optimal vibratome settings and correct handling of myocardial slices. Many aspects of cardiac structure and function can be studied using myocardial slices in vitro. Typical results obtained with hearts from a small mammal (rat) and a large mammal (human) with heart failure are shown, demonstrating myocardial slice viability, maximum contractility, Ca handling and structure. This protocol can be completed in ∼4 h.

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Section: Development and Applicationsmentioning

confidence: 99%

Preparation of viable adult ventricular myocardial slices from large and small mammals

et al. 2017

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“…[141–143], reviewed in [144]). By now, they have been employed in electrophysiology research, using extra- and intracellular potential recordings [145] and optical mapping techniques, including dual-dye (calcium and voltage) studies [146]. They have been tested for a range of cardiac tissue sources, from neonatal and adult rat to human [147].…”

Section: Ergomentioning

confidence: 99%

Fibroblast–myocyte electrotonic coupling: Does it occur in native cardiac tissue?

Kohl

Gourdie

2014

Journal of Molecular and Cellular Cardiology

164

141

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Heterocellular electrotonic coupling between cardiac myocytes and non-excitable connective tissue cells has been a long-established and well-researched fact in vitro. Whether or not such coupling exists in vivo has been a matter of considerable debate. This paper reviews the development of experimental insight and conceptual views on this topic, describes evidence in favour of and against the presence of such coupling in native myocardium, and identifies directions for further study needed to resolve the riddle, perhaps less so in terms of principal presence which has been demonstrated, but undoubtedly in terms of extent, regulation, patho-physiological context, and actual relevance of cardiac myocyte–non-myocyte coupling in vivo. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium."

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“…Cardiac tissues isolated from the hearts of different animal species have been widely used to conduct cardiac research using a range of biochemical, electrophysiological, pharmacological and morphological approaches, in order to assess the pro-arrhythmic potential of drugs (Akar & Rosenbaum, 2003; Bussek et al, 2012; Rosenbaum, 2001). While access to animal tissues is typically plentiful, the availability of human cardiac samples is limited.…”

Section: Introductionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

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Cardiac tissue slices with prolonged survival for in vitro drug safety screening

Cited by 27 publications

References 38 publications

Preparation of viable adult ventricular myocardial slices from large and small mammals

Preparation of viable adult ventricular myocardial slices from large and small mammals

Fibroblast–myocyte electrotonic coupling: Does it occur in native cardiac tissue?

Human ex-vivo action potential model for pro-arrhythmia risk assessment

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