Cardiovascular Toxicity Of Drugs Research Articles

Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells.

Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.

Recent Applications of Three Dimensional Printing in Cardiovascular Medicine.

Three dimensional (3D) printing, which consists in the conversion of digital images into a 3D physical model, is a promising and versatile field that, over the last decade, has experienced a rapid development in medicine. Cardiovascular medicine, in particular, is one of the fastest growing area for medical 3D printing. In this review, we firstly describe the major steps and the most common technologies used in the 3D printing process, then we present current applications of 3D printing with relevance to the cardiovascular field. The technology is more frequently used for the creation of anatomical 3D models useful for teaching, training, and procedural planning of complex surgical cases, as well as for facilitating communication with patients and their families. However, the most attractive and novel application of 3D printing in the last years is bioprinting, which holds the great potential to solve the ever-increasing crisis of organ shortage. In this review, we then present some of the 3D bioprinting strategies used for fabricating fully functional cardiovascular tissues, including myocardium, heart tissue patches, and heart valves. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro cardiovascular drug toxicity. Finally, we describe some applications of 3D printing in the development and testing of cardiovascular medical devices, and the current regulatory frameworks that apply to manufacturing and commercialization of 3D printed products.

Human Induced Pluripotent Stem-Cardiac-Endothelial-Tumor-on-a-Chip to Assess Anticancer Efficacy and Cardiotoxicity

Cancer remains a leading health threat in the United States, and cardiovascular drug toxicity is a primary cause to eliminate a drug from FDA approval. As a result, the demand to develop new anticancer drugs without cardiovascular toxicity is high. Human induced pluripotent stem (iPS) cell-derived tissue chips provide potentially a cost-effective preclinical drug testing platform, including potential avenues for personalized medicine. We have developed a three-dimensional microfluidic device that simultaneously cultures tumor cell spheroids with iPS-derived cardiomyocytes (iPS-CMs) and iPS-derived endothelial cells (iPS-EC). The iPS-derived cells include a GCaMP6 fluorescence reporter to allow real-time imaging to monitor intracellular calcium transients. The multiple-chambered tissue chip features electrodes for pacing of the cardiac tissue to assess cardiomyocyte function such as the maximum capture rate and conduction velocity. We measured the inhibition concentration (IC50) of the anticancer drugs, Doxorubicin (0.1 μM) and Oxaliplatin (4.2 μM), on the tissue chip loaded with colon cancer cells (SW620). We simultaneously evaluated the cardiotoxicity of these anticancer drugs by assessing the drug effect on the spontaneous beat frequency and conduction velocity of iPS-derived cardiac tissue. Consistent with in vivo observations, Doxorubicin reduced the spontaneous beating rate and maximum capture rate at or near the IC50 (0.04 and 0.22 μM, respectively), whereas the toxicity of Oxaliplatin was only observed at concentrations beyond the IC50 (33 and 9.9 μM, respectively). Our platform demonstrates the feasibility to simultaneously assess cardiac toxicity and antitumor effects of drugs and could be used to enhance personalized drug testing safety and efficacy. Impact statement Drug development using murine models for preclinical testing is no longer adequate nor acceptable both financially for the pharmaceutical industry as well as for generalized or personalized assessment of safety and efficacy. Innovative solutions using human cells and tissues provide exciting new opportunities. In this study, we report on the creation of a 3D microfluidic device that simultaneously cultures human tumor cell spheroids with cardiomyocytes and endothelial cells derived from the same induced pluripotent stem cell line. The platform provides the opportunity to assess efficacy of anticancer agents while simultaneously screening for potential cardiovascular toxicity in a format conducive for personalized medicine.

Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans.

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.

Plasma MiRNA-208b as a Biomarker for Detection of Cardiotoxicity Induced by Acute Cardiovascular Drugs Poisoning

Background: Poisoning by cardiovascular drugs has harmful effects and may lead to morbidity and mortality. In cases of myocardial injury, circulating miRNA-208 levels elevate after their leakage into the bloodstream at an early stage of myocardial insult. This study aims to assess the possible role of miRNA-208b in the early detection of myocardial injury in acute intoxicated patients with cardiovascular drugs such as digoxin, beta blockers and calcium channel blockers. Methods: This study enrolled 40 patients with cardiovascular drug toxicity admitted to the Poison Control Center of Ain Shams University Hospitals (PCC-ASUH) from January 2016 to December 2016 in addition to 40 healthy subjects as the normal control group. Blood samples for miRNA-208b determination and troponin were collected on admission for the patients group and in the early morning for the control group. The demographic and clinical data were collected for every patient. Results: Age and sex distribution revealed that most of studied patients were in the age group of 18- 24 years accounting for 50% with female predominance 85%. Beta blockers acute toxicity was the commonest cardiovascular drug toxicity (50%) followed by digitalis (35%) then calcium channel blockers (15%). The box plot outlook suggested that patients with a fold change in miRNA-208b higher than 1, was at risk of having a cardiac injury (ie. Troponin positive). Conclusion: This study concluded that miRNA-208b is a sensitive and specific biomarker in early detection of cardiac injury in patients with cardiovascular drugs poisonings for the early treatment of cardiotoxicity.

Comprehensive review of cardiovascular toxicity of drugs and related agents.

Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta‐blockers, calcium channel blockers, female hormones, nonsteroidal anti‐inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.

Intravenous fat emulsion: A potential novel antidote

Intravenous fat emulsions (IFE) are traditionally used as a component of parenteral nutrition therapy. Recently, IFE was used to resuscitate severe local anesthetic drug toxicity. This review focuses on the potential role of IFE in treatment of toxicity due to local anesthetics and other lipid-soluble drugs. The general properties of IFE, metabolic fate, and associated adverse events are described. Cases of local anesthetic toxicity treated with IFE are presented along with a discussion of the possible antidotal mechanisms. Initial investigations into the antidotal use of IFE for lipophilic central nervous and cardiovascular drug toxicity are also reviewed.

Toxicology training of paramedic students in the United States

A 16-item survey was mailed to the directors of 618 paramedic training programs in the United States to determine (1) the number of lecture hours devoted to toxicology topics and (2) how often paramedic training includes a rotation in a poison control center. The response rate was 82%. Toxicology accounts for approximately 2% of paramedic students' total training. Cardiovascular drug toxicity and hazardous materials are discussed for over 60 minutes by more than 50% of paramedic training programs. Four paramedic programs have no lecture time on cyclic antidepressant overdoses and one program has no lecture time on carbon monoxide poisoning. Eighty-one percent (377 of 467) have access to a regional poison control center; 11% (42 of 377) use the poison control center as a paramedic training site. Some US paramedic training programs spend insufficient time covering topics that have significant out-of-hospital morbidity. Although poison control centers are often available, they are underutilized for paramedic training.

Cardiopulmonary resuscitation in medical cancer patients: the experience of a medical intensive-care unit of a cancer centre.

This study aimed to determine the effectiveness and potential indications of cardiopulmonary resuscitation (CPR) in medical cancer patients, by retrospective analysis of the records of the patients admitted between November 1985 and January 1992 in the medical intensive-care unit of a cancer hospital following cardiac arrest. Cardiac arrest occurred in 49 cancer patients. CPR was successful in 19 (39%) but only 5 (10%) were discharged alive from the hospital. CPR was successful in all 8 patients in which cardiac arrest was the consequence of an acute cardiovascular drug toxicity, even if the cancer was metastatic and the purpose of treatment not curative, while it was effective in only 25% of those where cardiac arrest was an ultimate complication of various problems such as septic shock or respiratory failure complicating the neoplastic disease. The results suggest that in cancer, as in other types of disease, CPR is mainly indicated when cardiac arrest is the consequence of an acute insult.