Action Potential Kinetics

Cardiac Action Potential Kinetics (APD)

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The cardiac action potential is the sum of over 15 ionic currents, most of which can be altered by pharmacological compounds, and lead to adverse events such as QT interval prolongation. By analyzing changes in the morphology of the ventricular action potential, this assay verifies the direct interaction of a test article with all the channels involved in AP generation, and can point to the to the population of channels affected in the characteristics such as rate-dependence and pathological effects such as hypokalemia, hypothermia, etc. Finally, it is a robust system favorable to the generation of electrical events such as delayed- or early after-depolarizations (EADs).

Highlights:

  • Isolated  ventricular strips, trabeculae, papillary muscle, Purkinje fibres or cardiomyocytes
  • High-impedance microelectrode impalement
  • APD30, APD90, APD90-30, triangulation assessment
  • Rate-dependence assessment
  • Rat, guinea-pig, rabbit, dog hearts

Action Potential Kinetics analysis, AKA the Purkinje repolarisation assay

Pre-IND (GLP-compliant ) or exploratory designs (non-GLP compliant)

The cardiac action potential (AP) is the sum of over 15 ionic currents, most of which can be altered in the event of QT interval prolongation.  This test verifies the direct interaction of a test article with all the channels involved in the AP, and can point to the population of channels affected in the event of AP elongation.  The APD assay is useful in detecting and quantifying potentially pro-arrhythmic characteristics such as action potential triangulation, reverse rate-dependence, early-after depolarisations, etc.

Study Outline:

  • Number of tissues exposed to the test article: 5 tissues (screens 3 )
  • Number of concentrations of test article tested: 4 (screens 3 )
  • The model is easily adapted to reproduce disease characteristics of interest
  • Stimulation pattern: Electric field stimulation, variable frequencies of stimulation
  • A study includes positive, negative, and vehicle controls

Study Outcome:

  • A quantitative assessment of multiple-channel interactions (MICE) with the test article
  • Analytical dissection of the AP in pharmacologically relevant segments :VRest, VMax,  dV/dt, APD30, APD60 and APD90, APD90-30
  • Analysis of the incidence of triangulation, reverse-rate dependence, early-afterdepolarization events
  • FDA-ready hard copy  and e-report for electronic IND submission
  • Holistic interpretation of a positive signal, considering all other data generated

Recommended reading:

  1. Jalaie M. Holsworth DD., QT interval prolongation: and the beat goes on., Mini Rev Med Chem., 2005; 5(12):1083-91.
  2. Antzelevitch C. Oliva A., Amplification of spatial dispersion of repolarisation   underlies sudden cardiac death associated with catecholaminergic polymorphic  VT, long QT, short QT and Brugada syndromes., J. Intern Med., 2006; 259(1):48-58.