1. 1 Current Status and Future Challenges in Heart Transplantation Mark L. Barr, M.D. Associate Professor of Cardiothoracic Surgery Co-Director, Cardiothoracic Transplantation University of Southern California and Childrens Hospital, Los Angeles, CA

2. 2 The History Of Heart Transplantation 3 rd December 1967 Nearly 40 years and 70,000 transplants

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5. 5 Chemical Structure of Cyclosporin-A

6. 6 Orthotopic Implantation Positioning of donor heart Creation of left atrial anastomosis

7. 7 Orthotopic Implantation Completion of right atrial anastomosis (standard tchnique)

8. 8 Aortic anastomosis Pulmonary artery anastomosis Orthotopic Implantation

9. 9 Completed transplant Pacing wires on donor portion of right atrium and ventricle Pericardium left open

10. 10 Alternative Bicaval Approach Left atrial anastomosis performed Separate inferior and superior vena caval anastomosis

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12. 12 ISHLT/UNOS Registry Database Number of Transplants Performed ISHLT 2003 J Heart Lung Transplant 2003; 22: 610-72. Organ Transplants reported through 2001 Heart61,533 Heart-Lung2,935 Lung14,588

13. 13 Current Trends In Transplant Candidacy Older patients, > 65 years of age Generally sicker at time of transplant (Emergent (status 1A) or urgent transplants (status 1B) more common) More women (typically older at time of listing) More patients on mechanical circulatory devices 2004 OPTN/SRTR annual report.

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19. 19 Heart Transplantation Although NEVER subjected to a randomized control trial, heart transplantation is the ONLY therapy for advanced heart failure observationally associated with an excellent survival Advances in close follow-up and newer immunosuppression have led to improvement in 1 year survival close to 90% The problem is in survival beyond 1 year which is still limited (70% at 3 to 5 years, 50% at 10 years)

20. 20 Immunosuppression Management During Maintenance Phase LowBreakthrough rejection HighInfectionsMalignancies Therapeutic Nephrotoxicity Hypertension Diabetes Neurotoxicity 30 - 40% 30 - 55% 5 - 10% 10 - 30%

21. 21 Common Immunosuppressive Regimen in 2005 Primary: cyclosporine / tacrolimus (utilized in conjuction with therapeutic drug monitoring) Adjunctive: mycophenolate mofetil Supportive: prednisone (only 20 to 30% centers wean prednisone off if possible) Additive: statins (shown to be immunomodulatory and associated with improved long term survival)

22. 22 Source: 2005 OPTN/SRTR Annual Report. Trends in Maintenance Immunosuppression Prior to Discharge for Heart Transplantation, 1995-2004

23. 23 Major Post Transplant Complications Rejection Infection Cardiac allograft vasculopathy (CAV) Hypertension Nephrotoxicity Malignancy

24. 24 Rejection Invasive surveillance biopsies are the best established method for following patients Typically 13-15 biopsies are done in the first year Each biopsy requires a minimum of 3 samples from 3 different sites to be meaningful A new biopsy grading has been developed for widespread adoption

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27. 27 1990 Version International Society For Heart and Lung Transplantation Standardized Grading For Cardiac Biopsies Rejection gradeDescription 0No evidence of rejection 1 - Mild A - Focal Focal perivascular and/or interstitial infiltrate without myocyte damage B - DiffuseDiffuse infiltrate without myocyte damage 2 - Moderate (focal)One focus of infiltrate with myocyte damage 3 - Moderate A - Multifocal Multifocal infiltrate with myocyte damage Multifocal B - Diffuse Diffuse infiltrate with myocyte damage 4 - SevereDiffuse polymorphous infiltrate with extensive myocyte damage ± edema ± hemorrhage ± vasculitis

28. 28 GRADE 1A GRADE 2 GRADE 1B Mild

29. 29 GRADE 4 GRADE 3A GRADE 3B Threshold Mandatory For Therapy

30. 30 New Biopsy Grading Scale

31. 31 Acute Cellular Rejection R = Revised Stewart S, et al. JHLT 2005 in press Treatment required Acute Cellular Rejection 2004 proposed grade1990 ISHLT 0No rejection 1 RMildCombines former 1A, 1B, and 2 2 RModerateFormer 3A 3 RSevereFormer 3B and 4

32. 32 Incidence of BPR in Randomized Heart Transplant Immunosuppression Trials Trial 1st year published 1st year % patients with BPR Tac vs CSA (European) (n = 54; n = 28) 199873.7% vs 81.5% p = 0.444 (1yr) MMF vs Aza (n = 289; n = 289) 199845% vs 52.9% p = 0.055 (1yr) Tac vs CSA (US) (n = 39; n = 46) 199955% vs 44% p = 0.046 (6 mo) Neoral vs Sandimune (n = 188; n = 192) 199942.6% vs 41.7% p = ns (6 mo)

33. 33 Treatment of Rejection Rejection without hemodynamic compromise –Oral prednisone (100 mg daily for 3 days) –IV steroids –Decision dependent on grading severity and time post transplantation Steroid resistant rejection with or without hemodynamic compromise –Cytolytic antibodies; IVIG; plasmapheresis; photopheresis; anti-B cell antibodies; rapamycin; methotrexate; cyclophosphamide; total lymphoid irradiation

34. 34 Rejection Cellular rejection remains an important issue despite the incidence having declined over the past two decades Antibody mediated rejection is now recognized as an important entity but has not been previously standardized therefore not uniformly incorporated in trials of immunosuppressive therapy or investigations pertaining to transplantation

35. 35 Specific Causes of Death One Year After Cardiac Transplantation Kirklin JK, et al. J Thorac Cardiovasc Surg 2003; 125:881-90. Time after transplant (years) CRTD: 1990-1999, n = 7290 1 2 3 4 5 6 0.025 0.020 0.015 0.010 0.005 0.000 7 8 9 10 Deaths / year Rejection Infection Non-specific graft failure Neurologic Sudden Malignancy Allograft CAD

36. 36 Long Term Challenges Renal failure and metabolic adverse effects Cardiac allograft vasculopathy Malignancy

37. 37 Post-Heart Transplant Morbidity For Adults Cumulative Incidence for Survivors (Apr 1994 - Dec 2000) OutcomeBy 1 yearBy 5 years Hypertension72,4% (N = 12,496)95.1% (N = 3,465) Renal functionN = 12,511N = 3,776 Normal74.8%69.1% Renal dysfunction14.9%17.6% Creatinine > 2.5 mg/dL9.0%10.4% Chronic dialysis1.2%2.5% Renal transplant0.2%0.4% Hyperlipidemia48.7% (N = 13,183)81.3% (N = 3,899) Diabetes24.1% (N = 12,487)32.0% (N = 3,444) CAV8.2% (N = 11,260)33.2% (N = 2,376) ISHLT

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39. 39 Renal Function in Transplantation CRF developed in 16.5% Of these, 28.9% required maintenance dialysis or renal transplantation CRF significantly associated with increased risk of death –Relative risk = 4.55 –95% CI = 4.38 - 4.74 –p < 0.001 Ojo AO et al. N Engl J Med 2003; 349:931-40. 0.35 0.30 0.25 0.20 0.15 0.00 0.05 0.10 Time since transplantation (months) Cumulative incidence of CRF Intestine Live r Lung Heart Heart - lung 12243648607284961081200

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41. 41 The Problem Of Cardiac Allograft Vasculopathy Cardiac allograft vasculopathy (CAV) is the leading cause of death in cardiac transplant recipients at 5 years post-transplant, accounting for up to 30% of deaths CAV is characterized by a proliferation of the allograft vascular intima, resulting in narrowing of the vascular lumen Due to the lack of premonitory signs, CAV often presents as sudden death, silent myocardial infarction or severe arrhythmia

42. 42 Immune Factors Cellular Rejection score Antibody –mediated rejection Balance of Immunosuppression SMC EC NonImmune factors Mode of Brain Death Ischemia Reperfusion injury Hyperlipidemia Hypertension CMV infection Donor age Denuding injury Nondenuding injury PDGF, FGF, IGF TGF-ß, TNF, IL-1 MHC-II ICAM,VCAM IL-1, IL-2, IL-6, TNF PDGF, FGF, IGF, TGF-ß Platelets T-lymphocyte Macrophage selectins INFLAMMATION Mehra MR. AJT 2006 (in press)

43. 43 Maximal Intimal Thickening Predicts Cardiac Events Intimal thickening (mm) Mehra M et al. J Heart Lung Transplant 1995; 14:S207-11; Kobashigawa JA et al. J Am Coll Cardiol 2005; 45:1532-7; Tuzcu EM et al. J Am Coll Cardiol 2005; 45:1538-42. 0.35 0.50 1.00 0 Early Mid Late Normal Severe Abnormal Low High Moderate Risk of cardiac event Post- transplant time “Prognostically relevant” - High plaque burden - Link with cardiac events

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45. 45 Areas of Current Uncertainty and Future Research Regarding Malignancies in Heart Transplantation Relationship between different immunosuppressants and cancer risk Relationship between duration and intensity of immunosuppression and cancer risk Efficacy of low or minimal immunosuppression regimens Frequency of cancer screening Components of cancer screening Hauptman PJ and Mehra MR. J Heart Lung Transplant. 2005;24(8):1111-3.

46. 46 Effects on Human Tumor Cell Growth Growth inhibition (%) Hepatic cancerColorectal cancerMyelodysplasia Casadio F. Transplant Proc 2005; 37:2144.

47. 47 Heart Transplantation: 2005 and Beyond Need for improved immunosuppression with less rejection, cardiac allograft vasculopathy and side effects Need for better non-invasive methods to detect acute and chronic rejection Need to focus on improved survival and quality of life Challenges in performing long-term adequately powered multi-centered trials

48. 48 Acknowledgements Mandeep R. Mehra, MD Herbert Berger Professor of Medicine Head of Cardiology University of Maryland School of Medicine Patricia Uber, Pharm. D. Assistant Professor of Medicine Director for Best Practices University of Maryland Heart Center University of Maryland School of Medicine Sarah Miller Project Coordinator Scientific Registry of Transplant Recipients (SRTR) University of Michigan