1. 1 Hearts What makes an allograft marginal & Methods of evaluation: Hearts Steven SL Tsui Director of Transplantation, Papworth Hospital, Cambridge, U.K. British Transplant Society Congress 2010 Pre-congress Clinical Symposium Tuesday 16 th March 2010 Papworth Hospital NHS Foundation Trust NHS

2. 2 Heart Transplant Papworth Hospital NHS Foundation Trust NHS 1967 1 st successful HTx 1967 1 st successful HTx 1990 1980 2000 1970 2010 1979 1 st successful UK HTx 1979 1 st successful UK HTx Standard Donor Criteria Standard Donor Criteria

3. 3 NUMBER OF HEART TRANSPLANTS REPORTED BY YEAR ISHLT 2008 NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as evidence that the number of hearts transplanted worldwide has declined in recent years. J Heart Lung Transplant 2008;27: 937-983

4. 4 Heart Transplant Papworth Hospital NHS Foundation Trust NHS 1967 1 st successful HTx 1967 1 st successful HTx 1990 1980 2000 1970 2010 1979 1 st successful UK HTx 1979 1 st successful UK HTx Standard Donor Criteria Standard Donor Criteria

5. 5 Heart Transplant Papworth Hospital NHS Foundation Trust NHS 1967 1 st successful HTx 1967 1 st successful HTx 1990 1980 2000 1970 2010 1979 1 st successful UK HTx 1979 1 st successful UK HTx Standard Donor Criteria Standard Donor Criteria Older Donors Older Donors Longer Ischaemic Times Longer Ischaemic Times Valve Repair Valve Repair Hep C +VE Hep C +VE LV Hypertrophy LV Hypertrophy Coronary Disease Coronary Disease NHBD Drug Abuse Drug Abuse Brain Malignancy Brain Malignancy Cardiac Arrest Cardiac Arrest Poison

6. 6 Heart Transplant Rates 2006 Papworth Hospital NHS Foundation Trust NHS 2009 UK Heart Transplant Rate

7. 7 Variations in Heart Transplant Rates Heart donation rate Heart donation rate Yield rate: Yield rate: 19% to 62% (mean 39%) 1 19% to 62% (mean 39%) 1 Donor cause of death Donor cause of death Donor age Donor age Threshold for using marginal organs Threshold for using marginal organs Even in the most aggressive program, a significant % of donated hearts are not transplanted Even in the most aggressive program, a significant % of donated hearts are not transplanted 1 1999 survey by Assoc. of Organ Procurement Organizations (AOPO) Papworth Hospital NHS Foundation Trust NHS

8. 8 ADULT HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2006) ISHLT 2008 J Heart Lung Transplant 2008;27: 937-983 Papworth Hospital NHS Foundation Trust NHS

9. 9 Definition of High Risk Donor (HRD): Definition of High Risk Donor (HRD): Donor age > 40 yr Donor age > 40 yr High dose inotropes (dopamine > 12 μg.kg -1.min -1 ) High dose inotropes (dopamine > 12 μg.kg -1.min -1 ) CPR > 5 minutes CPR > 5 minutes Elevated CK-MB Elevated CK-MB D/R weight ratio < 80% D/R weight ratio < 80% Wall motion abnormality Wall motion abnormality Rhythm disturbances Rhythm disturbances Total ischemic time > 5 hrs Total ischemic time > 5 hrs HRD accounted for 38.3% of 188 heart transplants between 1985-92 in Oregon HRD accounted for 38.3% of 188 heart transplants between 1985-92 in Oregon A 1994 Definition of Marginal Donor Heart Ott et al. Ann Thorac Surg 1994;57:76-82 Papworth Hospital NHS Foundation Trust NHS

10. 10 Definition of Marginal Donor: Definition of Marginal Donor: Donor age > 55 years Donor age > 55 years cocaine or intravenous drug use cocaine or intravenous drug use diabetes mellitus diabetes mellitus hepatitis C +ve hepatitis C +ve EF < 45% EF < 45% D:R weight ratio < 0.7 D:R weight ratio < 0.7 UNOS Jan 1999 – Dec 2005: 13,024 heart transplants UNOS Jan 1999 – Dec 2005: 13,024 heart transplants Marginal donors, 10.2% of all Heart Tx in USA Marginal donors, 10.2% of all Heart Tx in USA A 2009 Definition of Marginal Donor Heart Russo et al. Ann Thorac Surg 2009;87:1066–71 Papworth Hospital NHS Foundation Trust NHS

11. 11 ADULT HEART TRANSPLANTS (1/2002-6/2006) Relative Risk of 1 Year Mortality with 95% Confidence Limits Donor Age 2008 ISHLT (N=8,823) J Heart Lung Transplant 2008;27: 937-983

12. 12 ADULT HEART TRANSPLANTS (1/2002-6/2006) Relative Risk of 1 Year Mortality with 95% Confidence Limits Donor BMI 2008 ISHLT (N=8,823) J Heart Lung Transplant 2008;27: 937-983

13. 13 ADULT HEART TRANSPLANTS (1/2002-6/2006) Relative Risk of 1 Year Mortality with 95% Confidence Limits Ischemia Time 2008 ISHLT (N=8,823) J Heart Lung Transplant 2008;27: 937-983

14. 14 ADULT HEART TRANSPLANTS (1/2002-6/2006) Factors Not Significant for 1 Year Mortality Recipient Factors: Prior malignancy, gender, hospitalized, prior pregnancy, balloon pump, diabetes, PRA Donor Factors: Clinical infection, history of diabetes, gender, history of hypertension, cause of death, history of malignancy Transplant Factors: HLA mismatch, CMV mismatch, prior transplant 2008 ISHLT J Heart Lung Transplant 2008;27: 937-983

15. 15 Organs that fail to meet 1 or more of the traditional criteria for an optimal cardiac donor Organs that fail to meet 1 or more of the traditional criteria for an optimal cardiac donor Consensus Conference Definition of Marginal Donor Heart 1 Zaroff et al. Circulation. 2002;106:836-841 Papworth Hospital NHS Foundation Trust NHS

16. 16 Extra Cardiac Factors Donor age < 55 y.o. Donor age < 55 y.o. Donor medical history Donor medical history Recent cardiac arrest Recent cardiac arrest Hep C +ve Hep C +ve Risk of coronary disease: smoking, hypertension, diabetes, lipids Risk of coronary disease: smoking, hypertension, diabetes, lipids Donor lifestyle Donor lifestyle Cocaine use Cocaine use IV drug abuse IV drug abuse Unprotected sex/multiple partners Unprotected sex/multiple partners Donor/recipient size mismatch Donor/recipient size mismatch Papworth Hospital NHS Foundation Trust NHS

17. 17 Structural Abnormalities Coronary artery disease Coronary artery disease LV hypertrophy LV hypertrophy Valvular abnormality Valvular abnormality Congenital lesions Congenital lesions Bicuspid AV Bicuspid AV Secundum ASD Secundum ASD Papworth Hospital NHS Foundation Trust NHS

18. 18 Functional Abnormalities Echocardiogram Echocardiogram EF > 45% EF > 45% Hemodynamic targets Hemodynamic targets CVP < 12 mmHg CVP < 12 mmHg PCWP < 12 mmHg PCWP < 12 mmHg MAP > 60 mmHg MAP > 60 mmHg C.I.> 2.4 L.min -1.m -2 C.I.> 2.4 L.min -1.m -2 SVR800 – 1200 dyne.sec -1.cm -5 SVR800 – 1200 dyne.sec -1.cm -5 Dopamine/dobutamine > 10 μg.kg -1.min -1 Dopamine/dobutamine > 10 μg.kg -1.min -1 Papworth Hospital NHS Foundation Trust NHS

19. 19 Donor Heart Assessment Biochemical Biochemical Structural Structural ECG ECG Echocardiogram Echocardiogram Coronary angiogram Coronary angiogram Functional Functional Echocardiogram Echocardiogram Invasive monitoring Invasive monitoring Papworth Hospital NHS Foundation Trust NHS

20. 20 Biochemical Markers CK-MB CK-MB Troponin Troponin Anderson et al. Transplantation. 1994;58:1056-57 Vijay et al. Ann Thorac Surg. 1998;66:1934-39 Pro-calcitonin Pro-calcitonin Venkateswaran et al. Transplantation. 2009;88:582-8 TNF-alpha TNF-alpha SMARCAL-1 SMARCAL-1 Aharinejad et al. Circulation. 2009;120:S198-205 Papworth Hospital NHS Foundation Trust NHS

21. 21 Structural Assessment ECG criteria ECG criteria S in V1 + R in V5/V6 > 35 mm Echocardiogram Echocardiogram Posterior wall or septum > 12 mm Posterior wall or septum > 12 mm Associated risk factors: Associated risk factors: History of hypertension History of hypertension Ischaemic time > 180 min. Ischaemic time > 180 min. 1 Marelli et al. J Heart Lung Transplant. 2000;19:496-503 Papworth Hospital NHS Foundation Trust NHS

22. 22 Coronary Angiography 1 Recommended: 1 Recommended: Male > 45 yr Male > 45 yr Female> 50 yr Female> 50 yr Consider in > 35 y.o. if Consider in > 35 y.o. if cocaine use cocaine use >2 risk factors >2 risk factors 2 Bench coronary cine-angiography 2 Bench coronary cine-angiography 1 Zaroff et al. Circulation. 2002;106:836-841 2 Robiscek et al. JTCVS 1992;102:490-5  Hypertension  Diabetes  Smoking  Dyslipidemia  Family history of CAD Papworth Hospital NHS Foundation Trust NHS

23. 23 Functional Assessment Serial echocardiogram Serial echocardiogram Stress echocardiogram 1 Stress echocardiogram 1 Dipyridamol Dipyridamol Dobutamine Dobutamine Invasive hemodynamic assessment Invasive hemodynamic assessment 1 Leone et al. J Heart Lung Transplant. 2009;28:1141-9 Papworth Hospital NHS Foundation Trust NHS

24. 24 Hemodynamic Monitoring Swan-Ganz provides: Preload- CVP / PCWP Preload- CVP / PCWP Afterload- SVR Afterload- SVR Cardiac output trends Cardiac output trends Papworth Hospital NHS Foundation Trust NHS Wheeldon et al. J Heart Lung Transplant 1995;14:734-8 Venkateswaran et al. Eur Heart J 2009;30:1771-80

25. 25 Principles of Donor Resuscitation: Papworth Protocol Achieve isovolaemia Achieve isovolaemia Acid-base balance Acid-base balance Powner et al. Prog Transplant 2000;10:25 Powner et al. Prog Transplant 2000;10:25 Minimise catecholamine Minimise catecholamine Hormone replacement Hormone replacement Novitzky et al. Transplantation. 1987;43:852-9 Vasopressin for: Pennefather et al. Transplantation 1990;49:311 Vasopressin for: Pennefather et al. Transplantation 1990;49:311 diabetes insipidus diabetes insipidus vascular tone vascular tone Wheeldon et al. J Heart Lung Transplant 1995;14:734-8 Zaroff et al. Circulation. 2002;106:836-41 Papworth Hospital NHS Foundation Trust NHS

26. 26 “…….. it makes little sense to replace one diseased heart with another.” N. DePasquale Editorial: how normal is the donor heart? Am Heart J 1969;77:719 ………….unless it can confer significant prognostic benefit to the recipient. Papworth Hospital NHS Foundation Trust NHS

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28. 28 The Alternate Recipient List for Heart Transplant 1 Laks et al. J Heart Lung Transplant. 1997;16:735-42 Standard Donor Heart Marginal Donor Heart Status 1 Patient Status 2 Patient Status 1 Patient Alternate Recipient since 1992 Papworth Hospital NHS Foundation Trust NHS

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30. 30 ADULT HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2006) CAUSE OF DEATH 0-30 Days (N = 3,006) 31 Days – 1 Year (N = 2,722) (N = 2,722) >1 Year – 3 Years (N = 2,135) >3 Years – 5 Years (N = 1,857) >5 Years – 10 Years (N = 4,054) >10 Years (N = 2,107) (N = 2,107) CARDIAC ALLOGRAFT VASCULOPATHY 52 (1.7%) 127 (4.7%) 298 (14.0%) 299 (16.1%) 581 (14.3%) 309 (14.7%) ACUTE REJECTION 193 (6.4%) 338 (12.4%) 220 (10.3%) 82 (4.4%) 69 (1.7%) 26 (1.2%) LYMPHOMA 2 (0.1%) 54 (2.0%) 85 (4.0%) 96 (5.2%) 195 (4.8%) 73 (3.5%) MALIGNANCY, OTHER 1 (0.0%) 57 (2.1%) 218 (10.2%) 340 (18.3%) 749 (18.5%) 392 (18.6%) CMV 4 (0.1%) 34 (1.2%) 16 (0.7%) 3 (0.2%) 5 (0.1%) 1 (0.0%) INFECTION, NON-CMV 393 (13.1%) 896 (32.9%) 276 (12.9%) 180 (9.7%) 442 (10.9%) 213 (10.1%) GRAFT FAILURE 1,257 (41.8%) 500 (18.4%) 499 (23.4%) 379 (20.4%) 765 (18.9%) 353 (16.8%) TECHNICAL 233 (7.8%) 28 (1.0%) 17 (0.8%) 17 (0.9%) 36 (0.9%) 20 (0.9%) OTHER 162 (5.4%) 175 (6.4%) 187 (8.8%) 147 (7.9%) 339 (8.4%) 175 (8.3%) MULTIPLE ORGAN FAILURE 356 (11.8%) 268 (9.8%) 117 (5.5%) 102 (5.5%) 309 (7.6%) 190 (9.0%) RENAL FAILURE 20 (0.7%) 25 (0.9%) 36 (1.7%) 65 (3.5%) 225 (5.6%) 173 (8.2%) PULMONARY 133 (4.4%) 108 (4.0%) 96 (4.5%) 85 (4.6%) 172 (4.2%) 99 (4.7%) CEREBROVASCULAR 200 (6.7%) 112 (4.1%) 70 (3.3%) 62 (3.3%) 167 (4.1%) 83 (3.9%) ISHLT Last updated based on data as of December 2006J Heart Lung Transplant 2008;27: 937-983

31. 31 ADULT HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2006) CAUSE OF DEATH 0-30 Days (N = 3,006) 31 Days – 1 Year (N = 2,722) (N = 2,722) >1 Year – 3 Years (N = 2,135) >3 Years – 5 Years (N = 1,857) >5 Years – 10 Years (N = 4,054) >10 Years (N = 2,107) (N = 2,107) CARDIAC ALLOGRAFT VASCULOPATHY 52 (1.7%) 127 (4.7%) 298 (14.0%) 299 (16.1%) 581 (14.3%) 309 (14.7%) ACUTE REJECTION 193 (6.4%) 338 (12.4%) 220 (10.3%) 82 (4.4%) 69 (1.7%) 26 (1.2%) LYMPHOMA 2 (0.1%) 54 (2.0%) 85 (4.0%) 96 (5.2%) 195 (4.8%) 73 (3.5%) MALIGNANCY, OTHER 1 (0.0%) 57 (2.1%) 218 (10.2%) 340 (18.3%) 749 (18.5%) 392 (18.6%) CMV 4 (0.1%) 34 (1.2%) 16 (0.7%) 3 (0.2%) 5 (0.1%) 1 (0.0%) INFECTION, NON-CMV 393 (13.1%) 896 (32.9%) 276 (12.9%) 180 (9.7%) 442 (10.9%) 213 (10.1%) GRAFT FAILURE 1,257 (41.8%) 500 (18.4%) 499 (23.4%) 379 (20.4%) 765 (18.9%) 353 (16.8%) TECHNICAL 233 (7.8%) 28 (1.0%) 17 (0.8%) 17 (0.9%) 36 (0.9%) 20 (0.9%) OTHER 162 (5.4%) 175 (6.4%) 187 (8.8%) 147 (7.9%) 339 (8.4%) 175 (8.3%) MULTIPLE ORGAN FAILURE 356 (11.8%) 268 (9.8%) 117 (5.5%) 102 (5.5%) 309 (7.6%) 190 (9.0%) RENAL FAILURE 20 (0.7%) 25 (0.9%) 36 (1.7%) 65 (3.5%) 225 (5.6%) 173 (8.2%) PULMONARY 133 (4.4%) 108 (4.0%) 96 (4.5%) 85 (4.6%) 172 (4.2%) 99 (4.7%) CEREBROVASCULAR 200 (6.7%) 112 (4.1%) 70 (3.3%) 62 (3.3%) 167 (4.1%) 83 (3.9%) ISHLT Last updated based on data as of December 2006J Heart Lung Transplant 2008;27: 937-983