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
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.
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.
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
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