Cardiotoxicity can be described as dysfunction of the heart stemming from exposure to drugs, pollutants, or other toxins. The irreversible 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 often causes higher drug attrition rates, 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.
Implanted telemetry remains the gold standard for cardiovascular electrophysiology studies in terms of signal quality and data coverage.
emka’s M series implants are uniquely adapted to toxicology studies. The implant is small and light, with a 2F pressure catheter designed for rats, guinea pigs, or small primates. In rats or guinea pigs, the implants can be placed subcutaneously or intraperitoneal.
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.. ECG leads come with solid tip for intravascular ECG.
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, a non-invasive 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. A restrainer keeps the subject in place while eliminating the needs for anesthesia, which can confound experimental results.
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, ecgTUNNEL 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.
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 versus indirect cardiac injury from cardiotoxic exposures/events. 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, which 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. Reductions in HRV are strongly correlated to heart disease.
HRV can be used very early (preclinically) to detect changes before permanent damage occurs which involve cardiomyopathy and heart failure. HRV can be assessed through invasive and non-invasive methods shown in the systems described above.
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