Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization

Terrar, Derek A.; Wilson, Carol M.; Graham, Sara; Bryant, Simon M.; Heath, Bronagh

doi:10.1016/j.vascn.2007.04.005

Cited by 42 publications

(35 citation statements)

References 29 publications

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“…Regulators will also require detailed doseresponse curves and inclusion of analytical standards that are industrially relevant. This will include readouts such as alterations in action potential duration (APD 30 ) to report on I Ca (caclium current) function and APD 40−90 (known as triangulation) on I K (potassium current) [4], and how these outputs relate to existing models. On the other hand, there are tremendous opportunities to improve safety by in vitro screening that will probably include hiPSC-derived genotypes from patients with known susceptibility to drugs.…”

Section: Discussionmentioning

confidence: 99%

“…However, the relationship between drug responses from animal-derived primary cardiomyocytes for in vitro assays or from tissue samples (e.g. guinea-pig ventricular myocytes) for ex vivo assays and their human counterparts is not always clear [4]. From the human heart itself, harvesting mature cardiomyocytes is confounded by limitations in cell numbers, proliferative capacity, variability in preparation, disease state and viability, especially from cadavers [2].…”

Section: Introductionmentioning

confidence: 99%

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Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

Dick

Rajamohan

Ronksley

et al. 2010

Biochemical Society Transactions

104

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Functional cardiomyocytes can now be derived routinely from hPSCs (human pluripotent stem cells), which collectively include embryonic and induced pluripotent stem cells. This technology presents new opportunities to develop pharmacologically relevant in vitro screens to detect cardiotoxicity, with a view to improving patient safety while reducing the economic burden to industry arising from high drug attrition rates. In the present article, we consider the need for human cardiomyocytes in drug-screening campaigns and review the strategies used to differentiate hPSCs towards the cardiac lineage. During early stages of differentiation, hPSC-cardiomyocytes display gene expression profiles, ultra-structures, ion channel functionality and pharmacological responses reminiscent of an embryonic phenotype, but maturation during extended time in culture has been demonstrated convincingly. Notably, hPSC-cardiomyocytes have been shown to respond in a highly predictable manner to over 40 compounds that have a known pharmacological effect on the human heart. This suggests that further development and validation of the hPSC-cardiomyocyte model as a tool for assessing cardiotoxicity is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

Dick

Rajamohan

Ronksley

et al. 2010

Biochemical Society Transactions

104

View full text Add to dashboard Cite

show abstract

“…Since these cells exhibit the ability to differentiate into various cells including cardiomyocytes, they hold great promise as an in vitro safety assessment tool to detect cardiotoxicity, such as QT-interval prolongation (2,3). In nonclinical drug development, we examine the activity of drug candidates on the key cardiac ion channels and action potential (AP) waveforms using animal-derived primary cardiomyocytes/tissues to predict the QT risk in the clinic (4,5); however, the drug responses from animal hearts may be different from human results because cardiomyocytes have distinct properties of ion channels among species (6,7). Therefore, using primary cardiomyocytes from animals would be a less relevant choice for predicting the arrhythmic risk in humans in the above-mentioned studies.…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Honda¹,

Kiyokawa²,

Tabo³

et al. 2011

J Pharmacol Sci

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Abstract. Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) hold great promise for development of in vitro research tools to assess cardiotoxicity, including QT prolongation. In the present study, we aimed to clarify the electrophysiological/pharmacological characteristics of hiPS-CMs using the patch-clamp technique. The hiPS cells were differentiated into beating cardiomyocytes by the embryoid body method. The expression of genes related to cardiac ion channels and differentiation markers in cardiomyocytes were detected by RT-PCR. Whole-cell patch-clamp recordings were performed using single hiPS-CMs dispersed from beating colonies. We confirmed voltage-dependence of major cardiac ion currents (I Na , I Ca , I Kr , and I Ks ) and pharmacological responses to ion-channel blockers. Action potential duration (APD) was prolonged by both I Kr /hERG and I Ks blockers, whereas it was shortened by an I Ca blocker, indicating that these ion current components contribute to action potential generation in hiPS-CMs. As for multiple ion channel blockers, terfenadine prolonged APD, but verapamil did not, results which were identical to clinically relevant pharmacological responses. These data suggest that patchclamp assay using hiPS-CMs could be an accurate method of predicting the human cardiac responses to drug candidates. This study would be helpful in establishing an electrophysiological assay to assess the risk of drug-induced arrhythmia using hiPS-CMs.

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“…These typically include studies to assess the effects of drug candidates on cardiac Purkinje fibers [47], studies on isolated cardiomyocytes either using electrophysiological recording of evoked action potentrials [48] and studies on ECG's and monophasic action potentials on Langendorff perfused isolated heart preparations [49,50]. These ex vivo measurements enable the assessment of proarrhythmic liability in the native environment of the cell where ion channels and other transport proteins are expressed naturally in the right stoichiometry with all the accessory subunits.…”

Section: Predicting Cardiac Arrhythmiasmentioning

confidence: 99%

“…This can be used as a model system to detect the pro-arrhythmic potential of drugs. Though technically challenging due to the myocyte preparation requirements, this method allows excellent perfusion of drugs and is less diffusion delimiting, hence allowing the accurate study of the effects of drugs on TAPs [48].…”

Section: Box 1 Cardiac Action Potentialmentioning

confidence: 99%

hERG (KCNH2 or Kv11.1) K+ Channels: Screening for Cardiac Arrhythmia Risk

Bowlby¹,

Peri²,

Zhang³

et al. 2008

CDM

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Testing new compounds for pro-arrhythmic potential has focused in recent years on avoiding activity at the hERG K+ channel, as hERG block is a common feature of many pro-arrhythmic compounds associated with Torsades de Pointes in humans. Blockers of hERG are well known to prolong cardiac action potentials and lead to long QT syndrome, and activators, although rarer, can lead to short QT syndrome. The most reliable assays of hERG utilize stable cell lines, and include ligand binding, Rb+ flux and electrophysiology (both automated and manual). These assays can be followed by measurement of activity at other ion channels contributing to cardiac contractility and detailed action potential/repolarization measurements in cardiac tissue. An integrated risk assessment for pro-arrhythmic potential is ultimately required, as the constellation of ion channel activities and potencies, along with the mechanism/kinetics of ion channel block, may ultimately be the best predictor of cardiac risk in vivo.

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Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization

Cited by 42 publications

References 29 publications

Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

hERG (KCNH2 or Kv11.1) K+ Channels: Screening for Cardiac Arrhythmia Risk

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