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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 The Fascination With Transplantation Has Existed For Centuries • Scientific Exchange • Financial pressures 1982: The Launch of the Society Journal Medium of Progress •The International Registry •Guidelines and position Statements Vienna Heroes KLEPETKO WOLNER LAUFER GRIMM WIESELTHALER ZUCKERMANN 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 Specific Causes of Death One Year After Cardiac Transplantation CRTD: 1990-1999, n = 7290 0.020 Deaths / year Renal Failure Rejection Infection Non-specific graft failure Neurologic Sudden 0.025 Malignancy 0.015 Allograft CAD 0.010 0.005 0.000 1 2 3 4 5 6 7 8 Time after transplant (years) Kirklin JK, et al. J Thorac Cardiovasc Surg 2003; 125:881-90. 9 10 9 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. 17-year-old heart transplant recipient 4 years post-transplantation 3 months later Immune factors Cellular rejection score Antibody-mediated rejection Balance of immunosuppression Platelet PDGF, FGF, IGF TGF-ß, TNF, IL-1 T-lymphocyte Macrophage SMC EC Denuding injury Non-denuding injury Non-immune factors Mode of brain death Ischemia reperfusion injury Hyperlipidemia Hypertension CMV infection Donor age INFLAMMATION MHC-II ICAM, VCAM Selectins IL-1, IL-2, IL-6, TNF PDGF, FGF, IGF, TGF-ß Mehra MR. Am J Transplant 2006; 6:1248-56. What’s Different In These Two Studies ? Maximal intimal thickness (MIT) predicts cardiac events Risk of cardiac event Low Moderate High Late Posttransplantation time Mid Early 0 0.35 Normal Abnormal Intimal thickening (mm) 0.50 1.00 “Prognostically relevant” - High plaque burden - Link with cardiac events Severe 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. IVUS Findings Versus Survival in Heart Transplantation Therapy Statins Attenuation of Intimal Thickening Modest Mycophenolate mofetil Modest Everolimus / sirolimus Marked Non – Immune Effects Survival (Duration Studied) Lipids Improved CRP (10 years) Rejection with HDC Neutral Improved Acute cellular rejection only Less CMV Rejection Rejection with HDC (3 years) No improveme Worse nt triglycerides and renal (4 years) function Mehra MR. Am J Transplant 2006 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?? Infection/Injury Pathogen-associated molecular patterns (PAMPs) Danger Signals Drive subsequent immune activation and Inflammation Adapted after: Medzhitov R, Janeway CA Jr: Science, 2002 Toll APC MHC/peptide TCR Co-stimulator CD28 Activation of the adaptive immune response Engraftment NON-IMMUNOLOGICAL FACTORS “DANGER SIGNALS” IMMUNE ACTIVATION “Danger Signals” RELATED INFLAMMATION VASCULOPATHY CLINICAL OUTCOME IMMUNOLOGICAL FACTORS 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 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 Smoking Kills The Cardiac Allograft Botha et al. American Journal of Transplantation 2008 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 A C B 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 Science is nothing but developed perception, interpreted intent, common sense rounded out and minutely articulated George Santayana, philosopher (1863 - 1952)