International Progress In Heart Transplantation

and The “Vienna Factor”

Mandeep R. Mehra, MDPresident , International Society For Heart and Lung Transplantation

Editor-in-Chief, Journal of Heart and Lung TransplantationHerbert Berger Chair in Medicine, Professor and Head of CardiologyAssistant Dean for Clinical Services, University of Maryland School of

MedicineBaltimore, 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 HeroesWOLNER

WIESELTHALER

LAUFER

ZUCKERMANN

KLEPETKO

GRIMM

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

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

0.0007 8 9 10

De

ath

s / y

ea

r

RejectionInfectionNon-specific graft failureNeurologicSudden

Malignancy

Allograft CAD

Renal Failure

MALIGNANCY POST-HEART TRANSPLANTATION FOR ADULTSCumulative Prevalence in Survivors (Follow-ups: April 1994 - June 2004)

123267115Other

Malignancy Type

15

40

423

625 (26.2%)

1757 (73.8%)

8-Year Survivors

Type Not Reported

Lymph

Skin

3947

115129

748249

1108 (16.1%)544 (3.1%)Malignancy (all types combined)

5753 (83.9%)17250 (96.9%)No Malignancy

5-Year Survivors

1-Year Survivors

Malignancy/Type

”Other” includes: prostate (11, 34, 21), adenocarcinoma (7, 4, 2), lung (5, 4, 1), bladder (4, 5, 5), sarcoma (3, 3, 1), breast (2, 8, 3), cervical (2, 4, 0), colon (2, 3, 3), and renal (2, 7, 2). Numbers in parentheses are those reported within 1 year, 5 years and 8 years, respectively.

ISHLT 2005J Heart Lung Transplant 2005;24: 945-982 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.

3 months later

17-year-old heart transplant recipient

4 years post-transplantation

Immune factorsCellular rejection scoreAntibody-mediated rejectionBalance of immunosuppression

SMC EC

Non-immune factorsMode of brain deathIschemia reperfusion injuryHyperlipidemiaHypertensionCMV infectionDonor age

Denudinginjury

Non-denudinginjury

PDGF, FGF, IGFTGF-ß, TNF, IL-1

MHC-IIICAM, VCAM

IL-1, IL-2, IL-6, TNFPDGF, FGF, IGF, TGF-ß

Platelet

T-lymphocyte

Macrophage

Selectins

INFLAMMATION

Mehra MR. Am J Transplant 2006; 6:1248-56.

What’s Different In These Two Studies ?

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 1.000

Early

Mid

Late

Normal

SevereAbnormal

LowHighModerate

Risk of cardiac event

Post-transplantation

time

“Prognostically relevant”- High plaque burden- Link with cardiac events

IVUS Findings Versus Survival in Heart Transplantation

Therapy Attenuation of Intimal

Thickening

Rejection Non – Immune Effects

Survival (Duration Studied)

Statins Modest Rejection with HDC

Lipids

CRP

Improved

(10 years)

Mycophenolate mofetil

Modest Rejection

with HDC

Neutral Improved

(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 2006Mehra 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??

Adapted after: Medzhitov R, Janeway CA Jr: Science, 2002

Danger SignalsDrive 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

IMMUNOLOGICAL FACTORS

CLINICAL OUTCOME

Engraftment

“Danger Signals”IMMUNE ACTIVATION

RELATED INFLAMMATION

NON-IMMUNOLOGICAL FACTORS

VASCULOPATHY

“DANGER SIGNALS”

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?

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

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

Mehra M et al. American Journal of Transplantation 2005Mehra 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

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

Science is nothing but developed perception, interpreted intent,

common sense rounded out and minutely articulated

George Santayana, philosopher (1863 - 1952)