Transcript Acute Decompensated Heart failure

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)