Dataset Information

Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.

ABSTRACT: Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the current preclinical models. Therefore, we sought to develop an adult human primary cardiomyocyte contractility model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic effect (sarcomere shortening) and generating multi-parameter data to profile different mechanisms of action based on cluster analysis of a set of 12 contractility parameters. We report that 17 positive and 9 negative inotropes covering diverse mechanisms of action exerted concentration-dependent increases and decreases in sarcomere shortening, respectively. Interestingly, the multiparametric readout allowed for the differentiation of inotropes operating via distinct mechanisms. Hierarchical clustering of contractility transient parameters, coupled with principal component analysis, enabled the classification of subsets of both positive as well as negative inotropes, in a mechanism-related mode. Thus, human cardiomyocyte contractility model could accurately facilitate informed mechanistic-based decision making, risk management and discovery of molecules with the most desirable pharmacological profile for the correction of heart failure.

SUBMITTER: Abi-Gerges N

PROVIDER: S-EPMC7203129 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.

Abi-Gerges Najah N Indersmitten Tim T Truong Ky K Nguyen William W Ratchada Phachareeya P Nguyen Nathalie N Page Guy G Miller Paul E PE Ghetti Andre A

Scientific reports 20200506 1

Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the current preclinical models. Therefore, we sought to develop an adult human primary cardiomyocyte contractility model that has the potential to provide a ...[more]

PMID: 32376974

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Project description:Cardiac safety remains the leading cause of drug development discontinuation. We developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk. Methods: Adult human primary cardiomyocytes from ethically consented organ donors were used to measure contractility transients. We used measures of changes in contractility parameters as markers to infer both drug-induced inotropic effect (sarcomere shortening) and pro-arrhythmia (aftercontraction, AC); contractility escape (CE); time to 90% relaxation (TR90). We addressed the clinical relevance of this approach by evaluating the effects of 23 torsadogenic and 10 non-torsadogenic drugs. Each drug was tested separately at four multiples of the free effective therapeutic plasma concentration (fETPC). Results: Human cardiomyocyte-based model differentiated between torsadogenic and non-torsadogenic drugs. For example, dofetilide, a torsadogenic drug, caused ACs and increased TR90 starting at 10-fold the fETPC, while CE events were observed at the highest multiple of fETPC (100-fold). Verapamil, a non-torsadogenic drug, did not change TR90 and induced no AC or CE up to the highest multiple of fETPCs tested in this study (222-fold). When drug pro-arrhythmic activity was evaluated at 10-fold of the fETPC, AC parameter had excellent assay sensitivity and specificity values of 96 and 100%, respectively. This high predictivity supports the translational safety potential of this preparation and of the selected marker. The data demonstrate that human cardiomyocytes could also identify drugs associated with inotropic effects. hERG channel blockers, like dofetilide, had no effects on sarcomere shortening, while multi-ion channel blockers, like verapamil, inhibited sarcomere shortening. Conclusions: Isolated adult human primary cardiomyocytes can simultaneously predict risks associated with inotropic activity and pro-arrhythmia and may enable the generation of reliable and predictive data for assessing human cardiotoxicity at an early stage in drug discovery.

Project description:Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K+, whereas high level of Mg2+ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine's contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.

Dataset Information

Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.

Publications

Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.

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