Leveraging the Langendorff Model to Detect Proarrhythmia
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The document discusses the assessment of proarrhythmic potential of test articles using various metrics in isolated rabbit hearts, focusing on the effects of E-4031. It details how E-4031 influences various parameters such as QRS duration, QT interval, MAPD90, and the incidence of early afterdepolarizations, all indicating increased vulnerability to arrhythmia. The findings emphasize the rate-dependent nature of these effects as concentration varies.
Leveraging the Langendorff Model to Detect Proarrhythmia
- 2. CorDynamics can use multiple approaches to examine effects of test articles on proarrhythmia Isolated Heart option - multiple indices as arbiters of increased vulnerability to arrhythmia during exposure to test articles - instantaneous monophasic action potential variability - Tpeak – Tend duration - QTpeak interval - monophasic action potential duration - incidence of early afterdepolarizations - rate dependence of all parameters
- 3. Effect of E-4031 on proarrhythmic potential - QRS duration (no change) and paced QT interval (increase) 80 70 60 50 40 30 20 10 0 Effect of E-4031 in Isolated Rabbit Heart QRS Interval CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 ms Concentration (μM) 450 400 350 300 250 200 150 100 50 0 Effect of E-4031 in Isolated Rabbit Heart QT Interval CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 ms Concentration (μM)
- 4. Effect of E-4031 on proarrhythmic potential - QTpeak interval (increase) and Tpeak – Tend duration (increase) -rate dependent 350 325 300 275 250 225 200 175 150 125 100 75 50 25 0 Effect of E-4031 in Isolated Rabbit Heart QTpeak Interval CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 ms Concentration (μM) 100 90 80 70 60 50 40 30 20 10 0 Effect of E-4031 in Isolated Rabbit Heart TpeakTend Interval CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 ms Concentration (μM)
- 5. Effect of E-4031 on proarrhythmic potential - MAPD90 (increase) and MAP triangulation (increase) - rate dependent 350 325 300 275 250 225 200 175 150 125 100 75 50 25 0 Effect of E-4031 in Isolated Rabbit Heart MAPD90 CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 ms Concentration (μM) 150 125 100 75 50 25 0 Effect of E-4031 in Isolated Rabbit Heart Triangulation CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 ms Concentration (μM)
- 6. Effect of E-4031 on proarrhythmic potential - incidence of early afterdepolarizations (increase) - rate dependent 60 55 50 45 40 35 30 25 20 15 10 5 0 Effect of E-4031 in Isolated Rabbit Heart EAD/min CL 750 ms (80 bpm) CL 500 ms (120 bmp) CL 250 ms (240 bpm) 0 0.1 1 10 counts Concentration (μM)