Cardiotoxicity can be described as dysfunction of the heart stemming from exposure to drugs, pollutants, or other toxins. The irresversible cardiac dysfunction and development of heart failure is characterized by electrophysiological, morphological and biochemical alterations. Cardiotoxicity is often associated with a decline in left ventricular ejection fraction (LVEF and autonomic disbalance).
Cardiovascular toxicity is an important cause of drug attrition, particularly for small molecule projects. The chronic administration of drugs, for example in cancer treatments, can also cause cardiac complications.
Electrocardiography analysis can provide deep insights into drug-induced myocardial pathology and help mitigate safety liabilities.
Inhaled particulate matter (PM) has recently been linked to a staggering 20% of mortality worldwide. Studies show chronic inhalation of particulate matter causes alterations in cardiac electrophysiology, and can lead to arrhythmias, oxidative stress, inflammation, vascular dysfunction, atherosclerosis, and heart failure. Pre-existing cardiovascular disease further increases the risk of adverse cardiac events following chronic PM exposure.
Functional cardiovascular outcomes such as electrocardiograms (ECGs), blood pressure and other hemodynamic endpoints can offer powerful insights into cardiac rhythm abnormalities associated with exposure to drugs and pollutants.
easyTEL+ Implanted telemetry
Implanted telemetry remains the gold standard for cardiovascular electrophysiology studies in terms of signal quality and data coverage.
emka’s M series implants is uniquely adapted to toxicology studies. The implant is small and light, with a 2F pressure catheter designed for rats, guinea pigs or small primates.
A 4.5F pressure catheter is available for large primates, dogs or other large animals. The implant can be placed subcutaneously in small primates or other large animal models for the acquisition of minimally invasive blood pressure, ECG, temperature, and activity signals. In rats or guinea pigs the implants can be placed subcutaneously or intraperitoneal. ECG leads come with solid tip for intravascular ECG.
emkaPACK4G – noninvasive jacketed telemetry
Repeat-dose toxicity studies can be carried out in large animals with external (jacketed) telemeters to provide a functional assessment of heart rhythm, conduction, repolarization and morphology, without the need for surgery.
Jacketed telemetry is often considered more sensitive and reproducible than traditional “snapshot” recordings in restrained animals, which are the mainstay of cardiovascular toxicity studies.
ecgTUNNEL – noninvasive, unanesthetized ECG for rodents
ecgTUNNEL, a restrained ECG research platform suitable for mice, hamsters and rats, can provide powerful insights into cardiac rhythm abnormalities associated with chronic exposure to drugs during longitudinal studies.
While rats are generally deemed unsuitable for QT interval assessments due to small ventricular hERG-like current, other ECG parameters such as heart rate, PR and QRS intervals can help uncover clinically relevant drug-induced cardiovascular effects.
Non-invasive ECG measurements can also reveal effects that intensify on repeated dosing. Therefore, it can replace or complement implanted telemetry studies in exploratory toxicology and repeat-dose toxicity studies, especially for research involving young mice or fragile knockout models where surgery is not an option.
Isolated heart perfusion system
The isolatedHEART preparation can be used to characterize pathogenetic mechanisms and uncover signs of altered heart function involved in cardiotoxicity.
The isolated perfused rat heart is especially useful in distinguishing direct vs. indirect cardiac injury from cardiotoxic exposures/events, as described by Peter G. Anderson et al. This preparation can also be used to plan subsequent in-vivo animal studies.
The Langendorff perfused heart is more suited for toxicologic studies than the working heart model because of the confounding effect of a contractile depression induced by the drug, that will produce reduced coronary perfusion and lead to ischemic injury.
Heart Rate Variability (HRV) is an important tool that can be used to characterize autonomic dysfunction. Autonomic tone and neurohumoral imbalance play very important roles in the development of heart disease and heart failure. HRV can be use very early (subclinically) to detect changes before permanent damage occurs which involve cardiomyopathy and heart failure. HRV can be assessed through invasive and non-invasive methods described by the systems described above.
Reductions in HRV are strongly correlated to heart disease.
Implants for large animals
Implants for rats
emkaPACK4G for large animals
Effect of metformin on ECG, HR and BP of rats administered with cardiotoxic agent doxorubicin
Emeka et al, International Journal of Basic & Clinical Pharmacology, 2017
Functional assessments in repeat-dose toxicity studies: the art of the possible
Will S. Redfern et al. Toxicology Research. 2013
Global mortality from outdoor fine particle pollution generated by fossil fuel combustion: Results from GEOS-Chem
Karn Vohra et al, Environmental Research. 2021
Non-invasive restrained ECG recording in conscious small rodents: a new tool for cardiac electrical activity investigation
H. Mongue-Din et al, Eur J Physiol, 2007
Integration of cardiac energetics, function and histology from isolated rat hearts perfused with doxorubicin and doxorubicin-ol; a model for use in drug safety evaluations
Kim Henderson et al. Journal of Pharmacological and Toxicological Methods.