Abstract
This study describes a rapid, cost-effective pre-clinical method to screen for pro- or antiarrhythmic effects of substances in an isolated heart preparation in line with the regulatory requirements of ICHS7B. The computational method “MFC method” quantifies arrhythmic episodes from isolated perfused hearts based on measuring the variation in the maximum force of contraction. Experiments were performed on hearts isolated from male Wistar rats. Arrhythmias were induced by the addition of tefluthrin or by ligation of the left coronary artery. The “MFC method” accurately measures the maximum force of every myocardial contraction and correlates it with the magnitude of the preceding beat. Arrhythmias were quantified by determining the coefficient of variation in the maximum force of contraction. This method is a useful approach to quickly identify the pro- or antiarrhythmic effects of drugs prior to more detailed analysis; particularly where the effects are varied and not easily classified under the Lambeth Conventions. Therefore, the “MFC method” can be used as a rapid screen for the antiarrhythmic effects of novel compounds or for rapidly determining potential cardiac toxicity.
Highlights
To be placed on the market in the European Union (EU), a medicinal product needs a marketing authorisation
Analysis of 22 isolated hearts revealed that for a 10-minute control period the mean coefficient of variation (CV) of the myocardial force of contraction (MFC) was 0.72 ± 0.066
Other investigators have studied the relationship between arrhythmic episodes and the Force of Contraction (FOC) of the heart [5], yet a review of literature in the public domain shows that such a method is not being used to study whether an investigational medicinal substance is arrythmogenic or not
Summary
To be placed on the market in the European Union (EU), a medicinal product needs a marketing authorisation. (a) Raw data of a 1-minute FOC control period as acquired by Chart v3.4.8.1®, (b) MFC of the raw data shown in (a) as analysed by the “MFC method,” (c) a 0.8-second insert zoom of the raw data shown in (a), (d) corresponding EGM of (c)
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