1. BBG 012 Study Procedures Rotterdam 23. January 2002

2. Patient Inclusion (1) Enrol from cath lab:  biplane and calibrated cineangiocardiography  no atrial fibrillation  no preceeding ES Refer to CRF-Pages 0 2

3. Patient Inclusion (2) Age  18 years Informed Consent Indicated for LV-Function Assessment  2 Segments with impaired EBD Refer to CRF-Pages 0 2

4. Patient Inclusion (3) Stratify to 3 different EF-Groups (based on onsite EF from cineangiocardiography) > 55 % 35- 54 % < 35 % enrol 5 patient in each EF-Category Refer to CRF-Pages 0 4

5. Patient Inclusion (3) Perform Study Echocardiography within 24 h to Cineangiocardiography Perform Cardiac MRI within 24 h before or 48 h post Study Echocardiography Refer to CRF-Pages 0 2

6. within 24 hours: Patient Information / Informed Consent Patient History, Concomitant Medications within 2 hours: Physical Examination Vital Signs 12 Lead ECG Procedures before study echocardiography Refer to CRF-Pages 0 5 0 9

7. M-Mode meaurements (parasternal SAX or LAX) a 4 CV a 2 CV a 3 CV SAX 5 cycles 1 DIGITAL 2 3 4 PreSet BBG 012 Native AQ – a4CV Start SonoVue Infusion at 1 ml per minute Use PreSet – BBG 012 – LVO – Adjust Infusion Rate If necessary administer additional Bolus (up to 2 ml single volume, up to 5 ml total volume Manual Infusion Pump 5 cycles 5 DIGITAL 6 7 8 a 4 CV a 2 CV a 3 CV SAX CK DIGITAL CK Refer to CRF-Pages UNENHANCED - LOOP 1-8 1 0

8. Start SonoVue Infusion (at 1 ml / min) a 4 CV a 2 CV a 3 CV SAX 5 cycles 9 DIGITAL 10 DIGITAL 11 DIGITAL 12 DIGITAL AQ – a4CV Start SonoVue Infusion at 1 ml per minute Use PreSet – BBG 012 – LVO – Adjust Infusion Rate If necessary administer additional Bolus (up to 2 ml single volume, up to 5 ml total volume Manual Infusion Pump 5 cycles 13 DIGITAL 14 DIGITAL 15 DIGITAL 16 DIGITAL a 4 CV a 2 CV a 3 CV SAX CK DIGITAL CK PreSet BBG 012 SonoVue Refer to CRF-Pages 1 SonoVue - LOOP 9-16

9. Continue with SonoVue Infusion (at optimal Infusion Rate) a 4 CV a 2 CV a 3 CV 2 flash replenishment cycles SVHS Start SonoVue Infusion at 1 ml per minute Use PreSet – BBG 012 – LVO – Adjust Infusion Rate If necessary administer additional Bolus (up to 2 ml single volume, up to 5 ml total volume Manual Infusion Pump DIGITAL PreSet TCE 3 Refer to CRF-Pages 1 2 MCE – Real Time Perfusion SVHS Offline Assesssment of EF, LV-Function, EBD, Wall Motion Assessment, Myocardial Perfusion Grading

10. within 2 hours: Physical Examination Vital Signs 12 Lead ECG Procedures after Study Echocardiography Refer to CRF-Pages 1 3 Post Study Examinations 1 4

11. Onsite Image Quality, Contrast Quality and EBD EF and LV-Volumes: visual (only EF), Simpsons method and aGSF Regional Wall Motion Analysis: Visual (aRSF supportive) M-Mode-Measurement for Left Chamber Perfusion Assessment Offsite Quality Control (E 1) Image Quality, Contrast Quality and EBD EF and LV-Volumes: visual (only EF), Simpsons method and aGSF Visual Regional Wall Motion Analysis (aRSF supportive) Efficacy-Evaluations Echocardiography

12. Grading Scale for Myocardial Perfusion CategoryGradeDescription Diagnostic Normal Perfusion N Rate of contrast filling is adequate and contrast uniformly fills the area (segment or region) Abnormal Perfusion X Perfusion defect Area shows an absence of contrast, regardless of the rate of contrast filling S Delayed perfusion Rate of contrast filling is slow, but contrast uniformly fills the area I Reduced perfusion Rate of contrast filling is adequate, but contrast filling is incomplete or patchy IS Reduced and delayed perfusion Rate of contrast filling is slow and contrast filling is incomplete or patchy Nondiagnostic AF Imaging artifact AT Contrast attenuation NV Segment not visualized IA Indeterminate assessment

13. LV-Volumes and EF WMA Segmental Evaluation Refer to CRF-Pages 2 Cineangiocardiography 2 4

14. Efficacy-Evaluations Cine Angiocardiography Onsite EF and LV-Volumes based on area-length or Simpsons method Visual Regional Wall Motion Analysis Assessement of CAD (15 Segment Model) Offsite Quality Control (CA 1) EF and LV-Volumes based on Simpsons method Visual Regional Wall Motion Analysis (automatic methods supportive)

15. LV-Volumes and EF WMA Segmental Evaluation Refer to CRF-Pages 2 6 Cardiac MRI

16. Efficacy-Evaluations Cardiac-MRI Onsite EF and LV-Volumes: based on tracking of subsequent short axis Visual Regional Wall Motion Analysis (Tagging supportive) Offsite EF and LV-Volumes: based on tracking of subsequent short axis Visual Regional Wall Motion Analysis (Tagging supportive)

17. Data Transfer Initialised and Labeled MOD from BBG SVHS Videotapes  Courier Service for transmission of MODs (Echo) and CDs (Cineangio + MRI) from Centre to Medidata  Transfer of CDs from Medidata to Offsite Readers

18. External Quality Control Rotterdam 23. January 2002 Quality Criteria Complete and transparent Digital Storage of Required Loops Correct Scanplanes Machine Settings Avoidable Artefacts