Arrhythmia Model

A limitation of the ICH-S7B guideline is that it specifically addresses repolarization delay with its well-known limitations to predict proarrhythmia risk and TdP. As a result of growing evidence against the use of QT interval as the primary endpoint for proarrhythmia liability, the interest in developing clinically relevant and predictable in vivo proarrhythmia models has increased. The anaesthetized, methoxamine-sensitized rabbit model of TdP developed by Carlsson (Carlsson et al, 1990; J. Cardiovasc. Pharmacology 16, 276-285) is a model that has been suggested to be of value in assessing drug-induced proarrhythmia liability. IonsGate Preclinical Services offers to test compounds in this model to assess their effects on ECG parameters and assess their potential proarrhythmic liabilities. Parameters obtained include:

  • Electrocardiogram (ECG) intervals
  • Proarrhythmic potential (Torsades de pointe, premature ventricular contractions, ventricular fibrillation, ventricular tachycardia and heart block)
  • Anti-arrhythmic potential

Arrhythmia_model

Heart Function: Left Ventricle Pressure-Volume Analysis (rats)

Left ventricular pressure-volume analysis in rats provides an extensive assessment of the cardiac safety and efficacy of novel compounds in vivo. Using this technique, pharmacologic effects on systolic and diastolic heart function are defined across a range of load-dependent and -independent parameters. Simultaneous arterial blood pressure measurements can evaluate direct hemodynamic effects. This technique can also be applied to perform proof of concept studies in a range of disease models. The IonsGate standard protocol uses SciSense Admittance PV-Catheter technology to accurately measure true volumes in real time. Parameters obtained include:

  1. End diastolic pressure-volume relationship (EDPVR)
  2. End systolic pressure-volume relationship (ESPVR or Ees)
  3. Preload recruitable stroke work (PRSW)
  4. End systolic and diastolic pressures and volumes (ESP, EDP, ESV, EDV)
  5. Stroke volume, ejection fraction, cardiac output, stroke work dP/dt max and dP/dt min
  6. Tau (relaxation)

PVloop

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