Transcript Document 7304878

Current Status and Future Challenges
in Heart Transplantation
Mark L. Barr, M.D.
Associate Professor of Cardiothoracic Surgery
Co-Director, Cardiothoracic Transplantation
University of Southern California and Childrens Hospital, Los Angeles, CA
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The History Of Heart Transplantation
3rd December 1967
Nearly 40 years and 70,000 transplants
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3
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Chemical Structure of Cyclosporin-A
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Orthotopic Implantation
• Positioning
of donor
heart
• Creation of
left atrial
anastomosis
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Orthotopic
Implantation
• Completion
of right atrial
anastomosis
(standard
tchnique)
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Orthotopic
Implantation
• Aortic
anastomosis
• Pulmonary
artery
anastomosis
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Orthotopic
Implantation
• Completed
transplant
• Pacing wires
on donor
portion of right
atrium and
ventricle
• Pericardium
left open
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Alternative
Bicaval
Approach
• Left atrial
anastomosis
performed
• Separate inferior
and superior
vena caval
anastomosis
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NUMBER OF HEART TRANSPLANTS
REPORTED BY YEAR
4500
3500
3000
2500
2000
4031
3157
1500
4389 4435 4358 4251
4157
3818
3547 3402
3340 3252
3135
3383
2718
2160
1000
1185
500
0
4196 4219
669
189
317
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90
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99
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00
20
01
20
02
20
03
Number of Transplants
.
4000
ISHLT
2005
NOTE: This figure includes only the heart transplants that are
reported to the ISHLT Transplant Registry. As such, this
should not be construed as evidence that the number of
hearts transplanted worldwide has declined in recent years.
J Heart Lung Transplant 2005;24: 945-982
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ISHLT/UNOS Registry Database
Number of Transplants Performed
Organ
Heart
Heart-Lung
Lung
Transplants reported
through 2001
61,533
2,935
14,588
ISHLT
2003
J Heart Lung Transplant 2003; 22: 610-72.
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Current Trends In Transplant Candidacy
• Older patients, > 65 years of age
• Generally sicker at time of transplant
(Emergent (status 1A) or urgent transplants
(status 1B) more common)
• More women (typically older at time of listing)
• More patients on mechanical circulatory
devices
2004 OPTN/SRTR annual report.
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ADULT HEART RECIPIENTS
Rehospitalization Post-transplant of Surviving Recipients
(Follow-ups: April 1994 - June 2004)
100%
80%
60%
40%
20%
No Hospitalization
Hospitalized: Rejection Only
Hospitalized: Rejection + Infection
Hospitalized: Not Rejection/Not Infection
Hospitalized: Infection Only
0%
Up to 1 Year
(N = 17,511)
ISHLT
Between 2 and 3 Years
(N = 14,928)
Between 4 and 5 Years
(N = 12,671)
Between 6 and 7 Years
(N = 9,920)
2005
J Heart Lung Transplant 2005;24: 945-982
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ADULT HEART RECIPIENTS
Functional Status of Surviving Recipients
(Follow-ups: April 1994 - June 2004)
100%
80%
60%
40%
20%
No Activity Limitations
Performs with Some Assistance
Requires Total Assistance
0%
1 Year (N = 15,901)
ISHLT
3 Years (N = 13,954)
5 Years (N = 11,872)
7 Years (N = 9,144)
2005
J Heart Lung Transplant 2005;24: 945-982
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Heart Transplantation
• Although NEVER subjected to a randomized
control trial, heart transplantation is the ONLY
therapy for advanced heart failure observationally
associated with an excellent survival
• Advances in close follow-up and newer
immunosuppression have led to improvement in
1 year survival close to 90%
• The problem is in survival beyond 1 year which is
still limited (70% at 3 to 5 years, 50% at 10 years)
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Immunosuppression Management During
Maintenance Phase
Low
High
Therapeutic
Breakthrough rejection
Infections
Malignancies
Nephrotoxicity
Hypertension
Diabetes
Neurotoxicity
30 - 40%
30 - 55%
5 - 10%
10 - 30%
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Common Immunosuppressive Regimen
in 2005
• Primary: cyclosporine / tacrolimus
(utilized in conjuction with therapeutic drug
monitoring)
• Adjunctive: mycophenolate mofetil
• Supportive: prednisone (only 20 to 30%
centers wean prednisone off if possible)
• Additive: statins (shown to be
immunomodulatory and associated with
improved long term survival)
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Trends in Maintenance Immunosuppression Prior to
Discharge for Heart Transplantation, 1995-2004
% Patients
100
Cyclosporine
Tacrolimus
80
60
40
20
0
1995
1996
1997
1998
Azathioprine
1999
2000
Year
2001
Mycophenolate mofetil
2002
2003
2004
Sirolimus
% Patients
100
80
60
40
20
0
1995
1996
1997
1998
Source: 2005 OPTN/SRTR Annual Report.
1999
2000
Year
2001
2002
2003
2004
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Major Post Transplant Complications
• Rejection
• Infection
• Cardiac allograft vasculopathy (CAV)
• Hypertension
• Nephrotoxicity
• Malignancy
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Rejection
• Invasive surveillance
biopsies are the best
established method for
following patients
• Typically 13-15 biopsies
are done in the first year
• Each biopsy requires a
minimum of 3 samples
from 3 different sites to
be meaningful
• A new biopsy grading
has been developed for
widespread adoption
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1990 Version
International Society For Heart and Lung Transplantation
Standardized Grading For Cardiac Biopsies
Rejection grade
Description
0
No evidence of rejection
1 - Mild
A - Focal
Focal perivascular and/or interstitial
infiltrate without myocyte damage
B - Diffuse
Diffuse infiltrate without myocyte damage
2 - Moderate (focal)
One focus of infiltrate with myocyte damage
3 - Moderate
A - Multifocal
Multifocal infiltrate with myocyte damage
Multifocal
B - Diffuse
4 - Severe
Diffuse infiltrate with myocyte damage
Diffuse polymorphous infiltrate with
extensive myocyte damage ± edema ±
hemorrhage ± vasculitis
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GRADE 1A
GRADE 1B
Mild
GRADE 2
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GRADE 3A
GRADE 3B
Threshold
Mandatory
For
Therapy
GRADE 4
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New Biopsy Grading Scale
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Acute
Cellular
Rejection
Acute
Cellular
Rejection
2004 proposed grade
1990 ISHLT
0
No rejection
No rejection
1R
Mild
Combines former 1A, 1B, and 2
2R
Moderate
Former 3A
3R
Severe
Former 3B and 4
Treatment required
R = Revised
Stewart S, et al. JHLT 2005 in press
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Incidence of BPR in Randomized Heart
Transplant Immunosuppression Trials
Trial
1st year
published
1st year % patients
with BPR
Tac vs CSA (European)
(n = 54; n = 28)
1998
73.7% vs 81.5%
p = 0.444 (1yr)
MMF vs Aza
(n = 289; n = 289)
1998
45% vs 52.9%
p = 0.055 (1yr)
Tac vs CSA (US)
(n = 39; n = 46)
1999
55% vs 44%
p = 0.046 (6 mo)
Neoral vs Sandimune
(n = 188; n = 192)
1999
42.6% vs 41.7%
p = ns (6 mo)
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Treatment of Rejection
• Rejection without hemodynamic compromise
– Oral prednisone (100 mg daily for 3 days)
– IV steroids
– Decision dependent on grading severity and time
post transplantation
• Steroid resistant rejection with or without
hemodynamic compromise
– Cytolytic antibodies; IVIG; plasmapheresis;
photopheresis; anti-B cell antibodies; rapamycin;
methotrexate; cyclophosphamide; total lymphoid
irradiation
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Rejection
• Cellular rejection remains an important issue
despite the incidence having declined over
the past two decades
• Antibody mediated rejection is now
recognized as an important entity but has not
been previously standardized therefore not
uniformly incorporated in trials of
immunosuppressive therapy or
investigations pertaining to transplantation
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Specific Causes of Death One Year
After Cardiac Transplantation
CRTD: 1990-1999, n = 7290
Rejection
Infection
Non-specific graft failure
Neurologic
Sudden
0.025
Deaths / year
0.020
Malignancy
0.015
Allograft CAD
0.010
0.005
0.000
1
2
3
4
5
6
7
8
9
10
Time after transplant (years)
Kirklin JK, et al. J Thorac Cardiovasc Surg 2003; 125:881-90.
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Long Term Challenges
• Renal failure and metabolic adverse effects
• Cardiac allograft vasculopathy
• Malignancy
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Post-Heart Transplant Morbidity For Adults
Cumulative Incidence for Survivors (Apr 1994 - Dec 2000)
Outcome
By 1 year
By 5 years
Hypertension
72,4% (N = 12,496)
95.1% (N = 3,465)
Renal function
N = 12,511
N = 3,776
Normal
74.8%
69.1%
Renal dysfunction
14.9%
17.6%
Creatinine > 2.5 mg/dL
9.0%
10.4%
Chronic dialysis
1.2%
2.5%
Renal transplant
0.2%
0.4%
Hyperlipidemia
48.7% (N = 13,183)
81.3% (N = 3,899)
Diabetes
24.1% (N = 12,487)
32.0% (N = 3,444)
8.2% (N = 11,260)
33.2% (N = 2,376)
CAV
ISHLT
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ADULT HEART TRANSPLANT RECIPIENTS:
Cause of Death (Deaths: January 1992 - June 2004)
Cause of death
0-30 days
(N = 2,984)
31 days - 1 yr
(N = 2,523)
> 1 yr - 3 yr
(N = 1,892)
> 3 yr - 5 yr
(N = 1,631)
> 5 yr
(N = 4,823)
Primary failure
26.3%
7.5%
6.6%
4.2%
4.3%
Multiple organ
failure
14.0%
10.1%
5.1%
5.8%
8.2%
Acute rejection
6.7%
12.1%
9.6%
4.1%
1.3%
Infection, non-cmv
12.9%
32.7%
13.3%
9.4%
10.0%
Coronary artery
vasculopathy
1.6%
4.6%
14.3%
16.9%
14.9%
Graft failure
13.9%
10.4%
16.6%
14.5%
13.9%
Renal failure
0.6%
0.8%
1.6%
3.6%
6.0%
Malignancy, other
0.1%
2.1%
10.3%
18.3%
18.3%
Lymphoma
0.1%
1.9%
4.3%
5.3%
4.6%
ISHLT
2005
J Heart Lung Transplant 2005;24: 945-982
38
Cumulative incidence of CRF
Renal Function in Transplantation
• CRF developed in 16.5%
0.35
0.30
Live
r
Lung
• Of these, 28.9% required
maintenance dialysis or
renal transplantation
Heart
• CRF significantly
associated with increased
risk of death
Intestine
0.25
0.20
0.15
0.10
Heart
- lung
0.05
– Relative risk = 4.55
0.00
0
12 24 36 48 60 72 84 96 108 120
Time since transplantation
(months)
– 95% CI = 4.38 - 4.74
– p < 0.001
Ojo AO et al. N Engl J Med 2003; 349:931-40.
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The Problem Of Cardiac Allograft
Vasculopathy
• Cardiac allograft vasculopathy (CAV) is the
leading cause of death in cardiac transplant
recipients at 5 years post-transplant, accounting
for up to 30% of deaths
• CAV is characterized by a proliferation of the
allograft vascular intima, resulting in narrowing
of the vascular lumen
• Due to the lack of premonitory signs, CAV often
presents as sudden death, silent myocardial
infarction or severe arrhythmia
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Immune Factors
Cellular Rejection score
Antibody –mediated rejection
Balance of Immunosuppression
SMC
Platelets
PDGF, FGF, IGF
TGF-ß, TNF, IL-1
T-lymphocyte
Macrophage
EC
Denuding
injury
Nondenuding
injury
NonImmune 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. AJT 2006 (in press)
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Maximal Intimal Thickening Predicts
Cardiac Events
Risk of cardiac event
Low
Moderate High
Late
Posttransplant
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
Mehra M et al. J Heart Lung Transplant 1995; 14:S207-11; Kobashigawa JA et al. J Am Coll Cardiol
2005; 45:1532-7; Tuzcu EM et al. J Am Coll Cardiol 2005; 45:1538-42.
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Areas of 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.
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Effects on Human Tumor Cell Growth
Growth inhibition (%)
100
CsA
Sirolimus
MPA
Leflunomide
75
50
25
Hepatic cancer
Colorectal cancer
Casadio F. Transplant Proc 2005; 37:2144.
HUVEC
THP-1
Jurkat
LoVo
HT-29
SW620
SW480
HEPG2
HuH-7
0
Myelodysplasia
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Heart Transplantation:
2005 and Beyond
• Need for improved immunosuppression with
less rejection, cardiac allograft vasculopathy
and side effects
• Need for better non-invasive methods to
detect acute and chronic rejection
• Need to focus on improved survival and
quality of life
• Challenges in performing long-term
adequately powered multi-centered trials
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Acknowledgements
• Mandeep R. Mehra, MD
Herbert Berger Professor of Medicine
Head of Cardiology
University of Maryland School of Medicine
• Patricia Uber, Pharm. D.
Assistant Professor of Medicine
Director for Best Practices
University of Maryland Heart Center
University of Maryland School of Medicine
• Sarah Miller
Project Coordinator
Scientific Registry of Transplant Recipients (SRTR)
University of Michigan
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