1. International Progress In Heart Transplantation and The “Vienna Factor” Mandeep R. Mehra, MD President, International Society For Heart and Lung Transplantation Editor-in-Chief, Journal of Heart and Lung Transplantation Herbert Berger Chair in Medicine, Professor and Head of Cardiology Assistant Dean for Clinical Services, University of Maryland School of Medicine Baltimore, MD Disclosures: consultant to Roche, Astellas, XDX, Novartis

2. The Fascination With Transplantation Has Existed For Centuries

3. Scientific Exchange Financial pressures

4. 1982: The Launch of the Society Journal

5. Medium of Progress The International Registry Guidelines and position Statements

6. Vienna Heroes WOLNER WIESELTHALER LAUFER ZUCKERMANN KLEPETKO GRIMM

7. Vienna Contributions Pharmacokinetics And Dynamics Of Novel Immunosuppression Genomic And Proteomic Biomarkers For Cardiac Rejection And Cardiac Allograft Vasculopathy Novel Aspects Of Mechanical Circulatory Support International Advocacy

8. 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 Renal Failure

9. 9

10. 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.

11. 3 months later 17-year-old heart transplant recipient 4 years post-transplantation

12. Immune factors Cellular rejection score Antibody-mediated rejection Balance of immunosuppression SMC EC Non-immune factors Mode of brain death Ischemia reperfusion injury Hyperlipidemia Hypertension CMV infection Donor age Denuding injury Non-denuding 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 Platelet T-lymphocyte Macrophage Selectins INFLAMMATION Mehra MR. Am J Transplant 2006; 6:1248-56.

13. What’s Different In These Two Studies ?

14. Maximal intimal thickness (MIT) predicts cardiac events Intimal thickening (mm) Kobashigawa JA et al. J Am Coll Cardiol 2005; 45:1532-7. Mehra M et al. J Heart Lung Transplant 1995; 14:S207-11. 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- transplantation time “Prognostically relevant” - High plaque burden - Link with cardiac events

15. IVUS Findings Versus Survival in Heart Transplantation TherapyAttenuation of Intimal Thickening RejectionNon – Immune Effects Survival (Duration Studied) StatinsModest Rejection with HDC Lipids CRP Improved (10 years) Mycophenolate mofetil Modest Rejection with HDC NeutralImproved (3 years) Everolimus / sirolimus Marked Acute cellular rejection only Less CMV Worse triglycerides and renal function No improveme nt (4 years) Mehra MR. Am J Transplant 2006

16. Multi-Detector Coronary CTA Sigurdsson G JACC 2006;48:772-8. –16 slice, n=54 >1.5 mm vessel, NPV 99%, PPV 81% Gregory SA AJC 2006;98:877-884. –64 slice, n=20, IVUS and QCA, IVUS NPV 77%, PPV 89% Limitations contrast, radiation Prognosis??

17. Adapted after: Medzhitov R, Janeway CA Jr: Science, 2002 Danger Signals Drive subsequent immune activation and Inflammation Infection/Injury Pathogen-associated molecular patterns (PAMPs) Toll APC MHC/peptide Co-stimulator TCR CD28 Activation of the adaptive immune response

18. IMMUNOLOGICAL FACTORS CLINICAL OUTCOME Engraftment “Danger Signals” IMMUNE ACTIVATION RELATED INFLAMMATION NON-IMMUNOLOGICAL FACTORS VASCULOPATHY “DANGER SIGNALS”

19. To cease smoking is the easiest thing I ever did….. I ought to know because I've done it a thousand times Mark Twain, 1905

20. Tobacco Exposure After Heart Transplantation: How Frequent? Mehra M et al. American Journal of Transplantation 2005 In 86 consecutive heart transplant recipients, 28 had evidence of significant tobacco exposure 32.5% rate of recrudescence –14 with urine positivity (denied exposure) –12 admitted exposure and had urine positivity –2 admitted to smoking but were not urine positive

21. Smoking Kills The Cardiac Allograft Botha et al. American Journal of Transplantation 2008

22. The Cardiac Allograft Is Going Up In Smoke: A Call to Action Mehra M et al. American Journal of Transplantation 2005 Mehra M. American Journal of Transplantation 2008 A Third of patients resume smoking after a heart transplant! Although advances in prevention of rejection allow median survival of 15 years, smokers reduce their average life span by 4.5 years Most deaths occur due to development of accelerated coronary artery disease and new cancers

23. A B C D A: Normal proximal tubular epithelial cells from a rat without cigarette smoke exposure; B: Swollen tubular epithelial cells, vacuoles, damaged glomerulus and fibrosis in a rat exposed to cigarette smoke for 30 days; C: normal glomerulus and D: completely damaged glomerulus in a rat exposed to cigarette smoke

25. Science is nothing but developed perception, interpreted intent, common sense rounded out and minutely articulated George Santayana, philosopher (1863 - 1952)