Drug-induced Cardiac Toxicity Research Articles

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e.g., DrugBank.ca and International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY) and was curated by 10 subject matter experts. The database includes information such as compound name, pharmacological mode of action, characterized cardiac mode of action, type of cardiac toxicity, known clinical cardiac toxicity profile, animal models used to evaluate the cardiotoxicity profile, routes of administration, and toxicokinetic parameters (i.e., Cmax). Data from both nonclinical and clinical studies are included for each compound. The user-friendly web interface allows for multiple approaches to search the database and is also intended to provide a means for the submission of new data/compounds from relevant users. This will ensure that the database is constantly updated and remains current. Such a data repository will not only aid the HESI working groups in defining drugs for use in any future studies, but safety scientists can also use the database as a vehicle of support for broader cardiovascular safety studies or exploring mechanisms of toxicity associated with certain pharmacological modes of action.

Drug-induced cardiac toxicity and adverse drug reactions, a narrative review

Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.

Real-Time Monitoring of Changes in Cardiac Contractility Using Silicon Cantilever Arrays Integrated with Strain Sensors.

This paper proposes the use of sensor-integrated silicon cantilever arrays to measure drug-induced cardiac toxicity in real time. The proposed cantilever sensors, unlike the conventional electrophysiological methods, aim to evaluate cardiac toxicity by measuring the contraction force of the cardiomyocytes corresponding to the target drugs. The surface of the silicon cantilever consists of microgrooves to maximize the alignment and the contraction force of the cardiomyocytes. This type of surface pattern also helps in the maturation of the cardiomyocytes by increasing the sarcomere length. The preliminary characterization of the cantilever sensors was performed on the cantilever surface, with the cardiomyocytes seeded with a density of 1000 cells/mm2, and the cardiac contractility was measured as a function of the culture days. The change in the contraction force of the cardiomyocytes due to the drug concentration was successfully measured through the integrated strain sensor in the culture media. The reliability of the sensor-integrated cantilevers and the feasibility of their mass production ensure that they meet the practical requirements in the medical applications.

Engineering spatial-organized cardiac organoids for developmental toxicity testing.

SummaryEmerging technologies in stem cell engineering have produced sophisticated organoid platforms by controlling stem cell fate via biomaterial instructive cues. By micropatterning and differentiating human induced pluripotent stem cells (hiPSCs), we have engineered spatially organized cardiac organoids with contracting cardiomyocytes in the center surrounded by stromal cells distributed along the pattern perimeter. We investigated how geometric confinement directed the structural morphology and contractile functions of the cardiac organoids and tailored the pattern geometry to optimize organoid production. Using modern data-mining techniques, we found that pattern sizes significantly affected contraction functions, particularly in the parameters related to contraction duration and diastolic functions. We applied cardiac organoids generated from 600 μm diameter circles as a developmental toxicity screening assay and quantified the embryotoxic potential of nine pharmaceutical compounds. These cardiac organoids have potential use as an in vitro platform for studying organoid structure-function relationships, developmental processes, and drug-induced cardiac developmental toxicity.

Enhancement of cardiac contractility using gold-coated SU-8 cantilevers and their application to drug-induced cardiac toxicity tests.

Herein, we propose an array of gold (Au)-coated SU-8 cantilevers with microgrooves for improved maturation of cardiomyocytes and describe its applications to drug-induced cardiac toxicity tests. Firstly, we evaluated the effect of cell culture substrates such as polydimethylsiloxane (PDMS), polyimide (PI), and SU-8 on the cardiomyocyte's maturation. Among these, the SU-8 with microgroove structures exhibits improved cardiomyocyte maturation. Further, thin layers of graphene and Au are coated on SU-8 substrates and the effects of these materials on cardiomyocyte maturation are evaluated by analyzing the expression of proteins such as alpha-actinin, Connexin 43 (Cx43), and Vinculin. While both conductive materials enhanced protein expression when compared to bare SU-8, the Au-coated SU-8 substrates demonstrated superior cardiomyocyte maturation. The cantilever structure is constructed using microgroove patterned SU-8 with and without an Au coating. The Au-coated SU-8 cantilever showed maximum displacement of 17.6 ± 0.3 μm on day 21 compared to bare SU-8 (14.2 ± 0.4 μm) owing to improved cardiomyocytes maturation. Verapamil and quinidine are used to characterize drug-induced changes in the contraction characteristics of cardiomyocytes on bare and Au-coated SU-8 cantilevers. The relative contraction forces and beat rates changed according to the calcium and sodium channel related drugs. Matured cardiomyocytes are less influenced by the drugs compared to immature cardiomyocytes and showed reliable IC50 values. These results indicate that the proposed Au-coated SU-8 cantilever array could help improve the accuracy of toxicity screening results by allowing for the use of cardiomyocytes that have been matured on the drug screening platform.

Novel concentration-QTc models for early clinical studies with parallel placebo controls: A simulation study.

The QTc interval of the electrocardiogram is a pharmacodynamic biomarker for drug-induced cardiac toxicity. The ICH E14 guideline Questions and Answers offer a solution for evaluating a concentration-QTc relationship in early clinical studies as an alternative to conducting a thorough QT/QTc study. We focused on covariance structures of QTc intervals on the baseline day and dosing day (two-day covariance structure,) and proposed a two-day QTc model to analyze a concentration-QTc relationship for placebo-controlled parallel phase 1 single ascending dose studies. The proposed two-day QTc model is based on a constrained longitudinal data analysis model and a mixed effects model, thus allowing various variance components to capture the two-day covariance structure. We also propose a one-day QTc model for the situation where no baseline day or only a pre-dose baseline is available and models for multiple ascending dose studies where concentration and QTc intervals are available over multiple days. A simulation study shows that the proposed models control the false negative rate for positive drugs and have both higher accuracy and power for negative drugs than existing models in a variety of settings for the two-day covariance structure. The proposed models will promote early and accurate evaluation of the cardiac safety of new drugs.

The virtual assay software for human in silico drug trials to augment drug cardiac testing

Prediction of drug effects on the heart still represents a challenge in drug development, given potential adverse outcomes. Computer modelling and simulations of the human heart offer a powerful technology to augment existing animal and clinical methodologies. Here we describe the translation process that led to the development and uptake of Virtual Assay, a user-friendly software to perform in silico drug trials in population of human cardiac models. Through this work, we contributed to the uptake of in silico modelling and simulations in industry and regulatory paradigms, and demonstrated accurate and mechanistic predictions of drug-induced cardiac pro-arrhythmic toxicity.

Cardiovascular disease during the COVID-19 pandemic: Think ahead, protect hearts, reduce mortality.

Coronavirus disease 2019 (COVID-19) is rapidly spreading globally. As of October 3, 2020, the number of confirmed cases has been nearly 34 million with more than 1 million fatalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for COVID-19. Newly diagnosed and worsening cardiovascular disease are common complications in COVID-19 patients, including acute cardiac injury, hypertension, arrhythmia, myocardial infarction, heart failure and sudden cardiac arrest. The mechanisms contributing to cardiac disease burden include hypoxemia, inflammatory factor storm, dysfunctional angiotensin converting enzyme 2 (ACE2), and drug-induced cardiac toxicity. Notably, the macrophages expressing ACE2 as direct host cells of SARS-CoV-2 secrete chemokine and inflammatory cytokines, as well as a decrease in cellular immune responses to SARS-CoV-2 infection due to elevated exhaustion levels and dysfunctional diversity of T cells, that may be accountable for the "hyperinflammation and cytokine storm syndrome" and subsequently acute cardiac injury and deteriorating cardiovascular disease in COVID-19 patients. However, no targeted medication or vaccines for COVID-19 are yet available. The management of cardiovascular disease in patients with COVID-19 include general supportive treatment, circulatory support, other symptomatic treatment, psychological assistance as well as online consultation. Further work should be concentrated on better understanding the pathogenesis of COVID-19 and accelerating the development of drugs and vaccines to reduce the cardiac disease burden and promote the management of COVID-19 patients, especially those with a severe disease course and cardiovascular complications.

Polymer-Based Functional Cantilevers Integrated with Interdigitated Electrode Arrays-A Novel Platform for Cardiac Sensing.

Heart related ailments are some of the most common causes for death in the world, and some of the causes are cardiac toxicity due to drugs. Several platforms have been developed in this regard over the years that can measure electrical or mechanical behavior of cardiomyocytes. In this study, we have demonstrated a biomedical device that can simultaneously measure electrophysiology and contraction force of cardiomyocytes. This dual-function device is composed of a photosensitive polymer-based cantilever, with a pair of metal-based interdigitated electrodes on its surface, such that the cantilever can measure the contraction force of cardiomyocytes and the electrodes can measure the impedance between cells and substrate. The cantilever is patterned with microgrooves so that the cardiomyocytes can align to the cantilever in order to make a higher cantilever deflection in response to contraction force. Preliminary experimental results have identified the potential for use in the drug-induced cardiac toxicity tests, and further optimization is desirable to extend the technique to various bio-sensor areas.

Highly durable crack sensor integrated with silicone rubber cantilever for measuring cardiac contractility

To date, numerous biosensing platforms have been developed for assessing drug-induced cardiac toxicity by measuring the change in contractile force of cardiomyocytes. However, these low sensitivity, low-throughput, and time-consuming processes are severely limited in their real-time applications. Here, we propose a cantilever device integrated with a polydimethylsiloxane (PDMS)-encapsulated crack sensor to measure cardiac contractility. The crack sensor is chemically bonded to a PDMS thin layer that allows it to be operated very stably in culture media. The reliability of the proposed crack sensor has been improved dramatically compared to no encapsulation layer. The highly sensitive crack sensor continuously measures the cardiac contractility without changing its gauge factor for up to 26 days (>5 million heartbeats), while changes in contractile force induced by drugs are monitored using the crack sensor-integrated cantilever. Finally, experimental results are compared with those obtained via conventional optical methods to verify the feasibility of building a contraction-based drug-toxicity testing system.

Micro-patterned SU-8 cantilever integrated with metal electrode for enhanced electromechanical stimulation of cardiac cells

Over the past few years, cardiac tissue engineering has undergone tremendous progress. Various in vitro methods have been developed to improve the accuracy in the result of drug-induced cardiac toxicity screening. Herein, we propose a novel SU-8 cantilever integrated with an electromechanical-stimulator to enhance the maturation of cultured cardiac cells. The simultaneous electromechanical stimulation significantly enhances the contraction force of the cardiomyocytes, thereby increasing cantilever displacement. Fluorescence microscopy analysis was performed to confirm the improved maturation of the cardiomyocytes. After the initial experiments, the contractile behaviors of the cultured cardiomyocytes were investigated by measuring the mechanical deformation of the SU-8 cantilever. Finally, the proposed electromechanical-stimulator-integrated SU-8 cantilever was used to evaluate the adverse effects of different cardiac vascular drugs, i.e., verapamil, lidocaine, and isoproterenol, on the cultured cardiomyocytes. The physiology of the cardiac-drug-treated cardiomyocytes was examined with and without electrical stimulation of the cardiomyocytes. The experimental results indicate that the proposed cantilever platform can be used as a predictive assay system for preliminary cardiac drug toxicity screening applications.

A Rising Hope of an Artificial Heart: Left Ventricular Assisted Device - Outcome, Convenience, and Quality of Life.

With the introduction of mechanical circulatory support, mainly continuous-flow left ventricular assisted devices (CF-LVAD), prolonging survival in end-stage heart failure patients can be seen in a new light. We also anticipate its use as a definitive therapy to overcome the limited donor organ resources for cardiac transplant. However, LVADs also have undesirable device-related complications and questionable improvement in the quality of life. In this review, we searched published articles using PubMed and Google Scholar to identify the complications and outcome of post-LVAD patients from 2014 to 2019. The studies we used included all study design types and a wide range of demographic variables focusing on age, sex, choice of LVAD as a bridge to cardiac transplant, or definitive therapy. For patients with New York Heart Association (NYHA) Class III B or IV or heart failure with reduced ejection fraction (HFrEF) with maximal medication therapy, there is a significant increase in mean ejection fraction from 4% to 6%. For patients with drug-induced cardiac toxicity or other causes of cardiac toxicity, with no significant risk factors, the ejection fraction increased to nearly 50% within 10-25 days of LVAD usage. There is also a substantial improvement in the quality of life in this literature review comparing to the pre-LVAD stage, as long as complications are taken into account. Data is limited for making an accurate judgment on the quality of life and functional capacity of LVADs. We found that the use of LVADs is not fully cost-effective, but still less financially burdening than a cardiac transplant. Although data from worldwide is limited and restricted to studies having a range of one to two years of follow-up, we conclude that LVADs are promising in improving cardiac function and the best bridging therapy available for patients waiting on a transplant.

Anti-hypotensive drug induced cardiotoxicity: an in vitro study.

Cardiotoxic side effects of broad range of drugs have emerged as an important cause of developing cardiovascular complications, as patients recover from one disease but develop another. Both cardiovascular and non-cardiovascular drugs may lead to the toxicity in the heart. Many drugs were initially not screened for cardiotoxicity, which is now an essential concern for drug discovery. Levophed is used for treating hypotension in critical care patients. Being a neurotransmitter, its concentration increases significantly in stress conditions and administration of this drug to patients' results in developing acute as well as persistent cardiac complications. Therefore, understanding its concentration-mediated effects and identifying the toxic concentration will serve as a platform to develop interventions to prevent adverse drug effects. In the present study, concentration and time-dependent effects of Levophed in H9C2 cardiomyoblasts were studied in detail by various cytotoxicity assays. Norepinephrine as a Levophed substitute was used and apoptotic cellular death was characterized by Annexin V and TUNEL DNA fragmentation assays. Morphological alterations, growth inhibition, and cellular death were also studied in detail. We observed that Levophed induces concentration-mediated deleterious effects in cardiomyoblasts. In-depth analysis of these effects will help in designing strategies in near future to combat and reduce this drug-induced cardiac toxicity.

Assessment of the drug-induced cardiac functional toxicity by pattern-cultured hiPSC-CMs

Assessment of the drug-induced cardiac functional toxicity by pattern-cultured hiPSC-CMs

Lung cancer as a cardiotoxic state: a review.

As the overall survival of patients with lung cancer continues to increase, more cancer survivors are faced with the risk of developing treatment-related cardiovascular toxicities. The increased knowledge of the molecular biology of non-small cell lung cancer has led to new and more personalized treatments. Nevertheless, the usual chemotherapy schemes and radiation therapy induce cardiac toxicities that are frequently underappreciated or go unnoticed. Up to date, the majority of cardiotoxicity studies have been focused in breast cancer, but new treatments in lung cancer patients, such as immune checkpoint-blocking antibodies or tyrosine kinase inhibitors, may also exert these cardiac toxic effects and therefore demand of the close collaboration of oncologists and cardiologists, in order to be addressed. The aim of this review is to provide more detailed information in regard to drug-induced cardiac toxicity focused in non-small cell lung cancer patients.

Screening, verification, and analysis of biomarkers for drug-induced cardiac toxicity in vitro based on RTCA coupled with PCR Array technology

Cardiotoxicity is one of the most serious side effects of new drugs. Early detection of the drug induced cardiotoxicity based on the biomarkers provides an important preventative strategy for detecting potential cardiotoxicity of candidate drugs. In this study, we aim to identify the predictive genomics biomarkers for drug-induced cardiac toxicity based on the RTCA coupled with PCR Array technology in primary cells. Three prototypical cardiotoxic compounds (doxorubicin, isoproterenol, ouabain) with different mechanisms were firstly real-time monitored to diagnose the cytotoxicity by using the RTCA, while the functional alterations of cardiomyocytes were also monitored by analyzing the beating frequency of cardiomyocytes. Then cardiac specific toxicity gene expression changes were studied by using the technology of PCR Array, which can detect the changes of 84 cardiac functions related genes. Rps6kb1 was identified to be the common cardiac biomarkers by using multivariate statistical and integration analyses. The biomarker was further verified by selecting other drugs with or without cardiotoxicity, and the results showed that the gene exhibited specific changes in cardiac toxicity. Moreover, IPA was applied to combine relevant pathways of Rps6kb1, and identify the main types of cardiac toxicity. These results would further enrich the evaluating strategy of drug-induced cardiotoxicity in vitro, and Rps6kb1 could be used as the specific biomarker of cardiotoxcity during safety assessment of the novel drug candidates.

Newer QT Correction Formulae to Correct QT for Heart Rate Changes During Exercise

BackgroundThe QT interval is a marker for drug-induced cardiac toxicity, electrolyte abnormalities and genetic mutations with a high risk of sudden death. AimThe objective was to determine the optimal QT-heart rate correction when heart rate is increased. Materials and MethodsA total of 40 persons had QT interval measured before at the end of each stage of a Bruce protocol. Currently used heart rate correction formulae (QTc) were compared to recently proposed QTc formulae derived from large population studies. ResultsComparing the data at each stage of exercise found that QTc using the Bazett formula (QTcBZT) increased with exercise while the QTc proposed by Fridericia (QTcFRD) and by Framingham (QTcFRM) decreased with exercise. In contrast QTc proposed by Dmitrienko (QTcDMT) and Rautaharju (QTcRTHa) were relatively constant despite the increase in heart rate during exercise, whereas QTc proposed by Hodges (QTcHDG) was more variable. With exercise, the differences between QTcBZT or QTcFRD and the other correction formulae became greater and highly significant. Next, the slope of QTc or RR regression was calculated for each individual during the exercise test. The rank order of the slopes (from the smallest to largest absolute value) was QTcRTHa, QTcDMT, QTcBZT, QTcHDG, QTcFRD and QTcFRM. Furthermore the slope of the QT/heart rate relationship was significantly (P < 0.0001) different between the older formulae proposed by Bazett or Fridericia compared to the newer formulae QTcDMT or QTcRTHa. ConclusionThe 2 newer QT-heart rate correction formula should be used when evaluating QT interval at faster heart rates especially those associated with exercise.

BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography.

Cardiotoxicity is a dose-limiting side-effect of cancer chemotherapeutics such as anthracyclines. The drug-induced cardiac toxicity is currently monitored with repeated assessments of the left ventricular ejection fraction (LVEF) using multigated equilibrium radionuclide ventriculography (MUGA) or echocardiography. However, the plasma cardiac biomarker B-type natriuretic peptide (BNP) has been suggested for early identification of cardiac dysfunction. The aim of the study was to compare LVEF obtained by MUGA and plasma BNP as predictors of developing congestive heart failure (CHF) or death in a population of anthracycline-treated cancer patients.MethodsWe prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow-up 2004-2010. Data were obtained from the Danish National Patient Registry.ResultsDuring follow-up (mean 1,360 days), 21 of the patients were admitted to hospital with a diagnosis of CHF and 194 of the patients died. BNP levels were significantly higher and LVEF lower in the group of patients that developed CHF. Using cut-off points of BNP>100 pg/ml (HR 5.5; CI 1.8–17.2; p = 0.003) and LVEF <50% (HR 7.9; CI 3.0–21.4; p<0.001) both significantly predicted CHF. Using the same cut-off points only BNP (HR 1.9; CI 1.3-2.9; p = 0.002) and not LVEF (HR 1.1; CI 0.7–1.8; p = 0.58) was predictive of overall death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death.ConclusionIn cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death.

Abstract C280: Oncology therapeutics show unique cardiotoxic profiles in human cardiac cells.

Abstract Tyrosine Kinase Inhibitors (TKI) have greatly improved the treatment and prognosis of multiple cancer types. However unexpected clinical cardiotoxicity has been shown with some of these agents that was not wholly predicted by current preclinical toxicity assessment methods. Since cardiotoxicity with TKI are often caused by the inhibition of signaling pathways critical to cardiac cell function, multi-targeted TKI that block multiple pathways increases the likelihood for cardiac cell damage. We recently demonstrated that an in vitro multi-parameter test panel assessing the effect of drug treatment on overall cardiac health and function could accurately predict the cardiotoxicity of 4 FDA-approved TKI. The 3 multi-targeted TKI clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the more targeted and relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. The present studies expand upon this initial observation to include other TKI, chemotherapeutic agents, and non-oncology compounds which were grouped based on their known clinical toxicity profiles ranging from cardiac safe to withdrawn. We then assessed the cardiotoxic potential of these compounds by examining their effect on cell viability, reactive oxygen species (ROS) generation, lipid formation, troponin secretion and beating activity in a human induced pluripotent-derived cardiac stem (iPS) cell model. The results showed a unique cardiotoxic signature of oncology therapeutics that was significantly different from other classes of drugs such as anti-arrhythmics. Oncology compounds induced potent cell death and lipid formation (metabolic stress) in iPS cells while anti-arrhythmics more potently disrupted cardiac cell beating with minimal impact on cell viability. In addition, troponin secretion was directly correlated with cardiac cell death for all of the oncology agents. In comparison, the cardiac-safe drugs, including non-oncology compounds and more targeted TKI, did not negatively affect any of the endpoints that assessed cardiac cell health and function. Thus different classes of drugs appear to show unique toxicity profiles that may reflect multiple mechanisms which lead to cardiotoxicity. Specifically our data suggest that more promiscuous TKI which inhibit the function of multiple oncogenic targets may be affecting pathways which are critical for cardiac cell health while more targeted agents are less cardiac toxic. These studies show that a multi-parameter approach can provide a robust characterization of drug-induced cardiac cell toxicity that can be leveraged to improve drug safety during early phase development. Furthermore, these studies emphasize the importance of developing more targeted oncology agents which are effective at killing cancer cells but lack toxic effects on cardiac cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C280. Citation Format: Dominique Talbert, Kimberly Doherty, Diarmuid Moran, Robert Wappell, Patricia Trusk, Scott Shell, Sarah Bacus. Oncology therapeutics show unique cardiotoxic profiles in human cardiac cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C280.

Assessing the translatability of In vivo cardiotoxicity mechanisms to In vitro models using causal reasoning

Drug-induced cardiac toxicity has been implicated in 31% of drug withdrawals in the USA. The fact that the risk for cardiac-related adverse events goes undetected in preclinical studies for so many drugs underscores the need for better, more predictive in vitro safety screens to be deployed early in the drug discovery process. Unfortunately, many questions remain about the ability to accurately translate findings from simple cellular systems to the mechanisms that drive toxicity in the complex in vivo environment. In this study, we analyzed translatability of cardiotoxic effects for a diverse set of drugs from rodents to two different cell systems (rat heart tissue-derived cells (H9C2) and primary rat cardiomyocytes (RCM)) based on their transcriptional response. To unravel the altered pathway, we applied a novel computational systems biology approach, the Causal Reasoning Engine (CRE), to infer upstream molecular events causing the observed gene expression changes. By cross-referencing the cardiotoxicity annotations with the pathway analysis, we found evidence of mechanistic convergence towards common molecular mechanisms regardless of the cardiotoxic phenotype. We also experimentally verified two specific molecular hypotheses that translated well from in vivo to in vitro (Kruppel-like factor 4, KLF4 and Transforming growth factor beta 1, TGFB1) supporting the validity of the predictions of the computational pathway analysis. In conclusion, this work demonstrates the use of a novel systems biology approach to predict mechanisms of toxicity such as KLF4 and TGFB1 that translate from in vivo to in vitro. We also show that more complex in vitro models such as primary rat cardiomyocytes may not offer any advantage over simpler models such as immortalized H9C2 cells in terms of translatability to in vivo effects if we consider the right endpoints for the model. Further assessment and validation of the generated molecular hypotheses would greatly enhance our ability to design predictive in vitro cardiotoxicity assays.