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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

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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

Assistant Dean for Clinical Services, University of Maryland School of Medicine

Baltimore, MD

Disclosures: consultant to Roche, Astellas, XDX, Novartis

slide3

Scientific Exchange

  • Financial pressures
medium of progress
Medium of Progress
  • The International Registry
  • Guidelines and position Statements
vienna heroes
Vienna Heroes

KLEPETKO

WOLNER

LAUFER

GRIMM

WIESELTHALER

ZUCKERMANN

vienna contributions
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
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.

current uncertainty and future research regarding malignancies in heart transplantation
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.

slide12

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.

maximal intimal thickness mit predicts cardiac events
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.

multi detector coronary cta
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??
slide17

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

slide18

Engraftment

“DANGER SIGNALS”

NON-IMMUNOLOGICAL

FACTORS

IMMUNOLOGICAL

FACTORS

IMMUNE ACTIVATION RELATED INFLAMMATION

“Danger Signals”

VASCULOPATHY

CLINICAL OUTCOME

slide19

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
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
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
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

slide23

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

slide25

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