Recognizing the nascent status of Comprehensive In Vitro Proarrhythmia Assay (CiPA), earlier this year we redesigned our standard rabbit Langendorff isolated heart assessments to be conducted with a much greater emphasis on proarrhythmia – while still capturing vital details on cardiac hemodynamics, electrocardiography, and electrophysiology.

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)