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International Progress In Heart Transplantation and The “Vienna Factor”

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

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International Progress In Heart Transplantation and The “Vienna Factor”

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  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 KLEPETKO WOLNER LAUFER GRIMM WIESELTHALER ZUCKERMANN

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

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  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 4 years post-transplantation 17-year-old heart transplant recipient

  12. Platelet PDGF, FGF, IGF TGF-ß, TNF, IL-1 T-lymphocyte Macrophage Denuding injury INFLAMMATION Non-denuding injury MHC-II ICAM, VCAM Selectins IL-1, IL-2, IL-6, TNF PDGF, FGF, IGF, TGF-ß 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 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 Risk of cardiac event Low Moderate High Late Post-transplantation time Mid Early “Prognostically relevant” - High plaque burden - Link with cardiac events 0 0.35 0.50 1.00 Normal Abnormal Severe 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.

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

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

  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? • 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 Mehra M et al. American Journal of Transplantation 2005

  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 • 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 Mehra M et al. American Journal of Transplantation 2005 Mehra M. American Journal of Transplantation 2008

  23. B A 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

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

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