Background: Predicting cardiac toxicity is one of the most important challenges in drug discovery. Over the past 25 years, several non-cardiac drugs got under investigation due to increased morbidity and mortality associated with adverse cardiac events, such as life-threatening arrhythmias. More than 100 clinically used drugs belonging to a variety of unrelated classes were marked as possibly proarrhythmic, leading to removal of drugs from the market in some cases. The International Conference on Harmonization (ICH) firmly advocates that preclinical and clinical tests for hemodynamic effects and proarrhythmic potential be performed for all drug candidates prior to approval by government regulatory agencies, regardless of the intended therapeutic application.

The Langendorff heart is the only comprehensive assay capable of evaluating both electrophysiological parameters and the hemodynamic effects of a compound. This model is a physiologically relevant bridge between in vitro assays and in vivo studies. The Langendorff heart has proven to be highly correlated to in vivo approaches and highly predictive of in vivo effects.

The isolated heart perfused with increasing concentrations of test articles is also useful for measuring spontaneously-beating or stimulated hearts RR, PR, QRS, QT, QTc intervals of ECG, left ventricle contraction, heart rate, blood pressure. We also employ this tool as an ischemia reperfusion model in drug discovery investigations.

Service details: The isolated Langendorff heart is employed in our cardiovascular studies for: prolonged QT Interval, Heart Rate, Blood Pressure, ECG, as well as lead compounds screening for cardiovascular effects.

  • Source: rat, guinea pig, rabbit.
  • Number of hearts exposed to the test article: 6 hearts;
  • Number of concentrations of test article tested: 4 or more;
  • The model can be surgically altered to reproduce disease characteristics of interest;
  • Stimulation: variable frequencies of stimulation or spontaneously beating hearts;
  • A study includes positive, negative, and vehicle controls.

Deliverable: The main parameters estimated are: mean EC 50(MFF) – average of effective concentration of the drug reducing MFF by 50% in the atrial preparations tested; mean TC50(IR) – average of the toxic concentration of the drug reducing inotropic response (contraction) by 50% in the right atrial preparations tested; mean TC 50(CR) – average of the toxic concentrations of the drug reducing chronotropic response (atrial rate) by 50% in the right atrial preparations tested.  Final report includes methodology, raw data, graphs (if necessary) and interpretation.