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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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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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• Aortic anastomosis
• Pulmonary artery anastomosis
Orthotopic Implantation
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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
189 317669
1185
2160
2718
31573383
4031 4196 42194389 4435 4358 4251 4157
38183547 3402 3340 3252 3135
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Nu
mb
er o
f T
ran
spla
nts
.
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 11
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ISHLT/UNOS Registry DatabaseNumber of Transplants Performed
ISHLT 2003J Heart Lung Transplant 2003; 22: 610-72.
OrganTransplants reported
through 2001
Heart 61,533
Heart-Lung 2,935
Lung 14,588
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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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H E A R T T R A N S P L A N T A T IO NK a p la n -M e ie r S u r v iv a l (1 /1 9 8 2 -6 /2 0 0 3 )
0
2 0
4 0
6 0
8 0
1 0 0
0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1
Y e a rs
Su
rviv
al
(%)
.
H a lf -li fe = 9 .6 y e a r sC o n d itio n a l H a lf -li fe = 1 2 y e a r s
N = 6 6 ,7 5 1
IS H L T 2005
N fo l lo w e d a t lo n g e s t t im e p o in t : 2 5 ,9 0 8
J H e a r t L u n g T ra n s p la n t 2 0 0 5 ;2 4 : 9 4 5 -9 8 2 14
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AD U LT H E AR T TR AN S PLAN TA TIO NK aplan -M eier S urviva l by E ra (Transplants: 1/1982 – 6/2003)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Y ears
1 98 2 -1 98 8 (N= 9 ,1 48 )
1 98 9 -1 99 3 (N= 1 7,89 8 )
1 99 4 -1 99 8 (N= 1 8,71 4 )
1 99 9 -6 /2 00 3 (N= 1 3,48 0 )
All com parisons sign ifican t a t p < 0 .01
HAL F -L IF E 1 9 82 -1 9 88 : 8 .1 y ea rs ; 1 98 9 -1 99 3 : 9 .5 y e a rs ; 1 9 9 4-19 9 8: 9.8 ye a rs
Su
rviv
al (
%)
IS H LT 2005J H eart Lung T ransplant 2005;24: 945 -982 15
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A D U L T H E A R T T R A N S P L A N T A T IO NK a p la n -M e ie r S u rv iv a l b y V A D u s a g e (T ra n s p la n ts : 1 /1 9 9 9 -6 /2 0 0 3 )
50
60
70
80
90
1 00
0 1 2 3 4 5
Y e a r s
Su
rviv
al (
%)
H e a r tm a te /N o v a c o r (N= 1 ,0 5 5 ) No L V A D (N= 7 ,0 0 0 )
p = 0 .0 2 2
IS H L T 2005
N o te : O n ly 3 2 tra n s p la n ts in v o lv in g c o n t in u o u s f lo w d e v ic e s a n d 3 3 w ith E C M O ; to o fe w to a n a ly z e .
J H e a r t L u n g T ra n s p la n t 2 0 0 5 ;2 4 : 9 4 5 -9 8 2 16
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ADULT HEART RECIPIENTSRehospitalization Post-transplant of Surviving Recipients
(Follow-ups: April 1994 - June 2004)
0%
20%
40%
60%
80%
100%
Up to 1 Year (N = 17,511)
Between 2 and 3 Years (N = 14,928)
Between 4 and 5 Years (N = 12,671)
Between 6 and 7 Years (N = 9,920)
No Hospitalization Hospitalized: Not Rejection/Not InfectionHospitalized: Rejection Only Hospitalized: Infection OnlyHospitalized: Rejection + Infection
ISHLT 2005J Heart Lung Transplant 2005;24: 945-982 17
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ADULT HEART RECIPIENTSFunctional Status of Surviving Recipients
(Follow-ups: April 1994 - June 2004)
0%
20%
40%
60%
80%
100%
1 Year (N = 15,901) 3 Years (N = 13,954) 5 Years (N = 11,872) 7 Years (N = 9,144)
No Activity Limitations Performs with Some Assistance Requires Total Assistance
ISHLT 2005J Heart Lung Transplant 2005;24: 945-982 18
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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 Breakthrough rejection
High Infections Malignancies
Therapeutic
NephrotoxicityHypertension
DiabetesNeurotoxicity
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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0
20
40
60
80
100
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004Year
% P
atie
nts
Cyclosporine Tacrolimus
Source: 2005 OPTN/SRTR Annual Report.
0
20
40
60
80
100
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004Year
% P
atie
nts
Azathioprine Mycophenolate mofetil Sirolimus
Trends in Maintenance Immunosuppression Prior to Discharge for Heart Transplantation, 1995-2004
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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 VersionInternational Society For Heart and Lung
TransplantationStandardized 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 - ModerateA - Multifocal
Multifocal infiltrate with myocyte damage
MultifocalB - Diffuse
Diffuse infiltrate with myocyte damage
4 - Severe Diffuse polymorphous infiltrate with extensive myocyte damage ± edema ± hemorrhage ± vasculitis
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GRADE 1A
GRADE 2
GRADE 1B
Mild
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29GRADE 4
GRADE 3A GRADE 3B
ThresholdMandatory
ForTherapy
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New Biopsy Grading Scale
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Acute Cellular Rejection
R = RevisedStewart S, et al. JHLT 2005 in press
Treatment required
Acute Cellular Rejection
2004 proposed grade 1990 ISHLT
0 No rejection No rejection
1 R Mild Combines former 1A, 1B, and 2
2 R Moderate Former 3A
3 R Severe Former 3B and 4
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Incidence of BPR in Randomized Heart Transplant Immunosuppression Trials
Trial1st year
published1st 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
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
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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 AdultsCumulative 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)
CAV 8.2% (N = 11,260) 33.2% (N = 2,376)
ISHLT
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ADULT HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2004)
8.2%5.8%5.1%10.1%14.0%Multiple organ failure
14.9%16.9%14.3%4.6%1.6%Coronary artery vasculopathy
1.3%4.1%9.6%12.1%6.7%Acute rejection
> 3 yr - 5 yr (N = 1,631)
31 days - 1 yr (N = 2,523)
13.9%14.5%16.6%10.4%13.9%Graft failure
10.0%9.4%13.3%32.7%12.9%Infection, non-cmv
4.6%5.3%4.3%1.9%0.1%Lymphoma
18.3%18.3%10.3%2.1%0.1%Malignancy, other
6.0%
4.3%
> 5 yr (N = 4,823)
3.6%
4.2%
0.8%
7.5%
1.6%0.6%Renal failure
6.6%26.3%Primary failure
> 1 yr - 3 yr (N = 1,892)
0-30 days
(N = 2,984)Cause of death
ISHLT 2005J Heart Lung Transplant 2005;24: 945-982
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Renal Function in Transplantation
• CRF developed in 16.5%
• Of these, 28.9% required maintenance dialysis or renal transplantation
• CRF significantly associated with increased risk of death
– Relative risk = 4.55
– 95% CI = 4.38 - 4.74
– p < 0.001
Ojo AO et al. N Engl J Med 2003; 349:931-40.
0.35
0.30
0.25
0.20
0.15
0.00
0.05
0.10
Time since transplantation (months)
Cu
mu
lati
ve i
nci
den
ce o
f C
RF
IntestineLive
rLung
Heart
Heart- lung
12 24 36 48 60 72 84 96 108 1200
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A D U L T H E A R T T R A N S P L A N T A T IO N K a p la n -M e ie r S u rv iv a l fo r K id n e y a fte r H e a rt T ra n s p la n ts C o m p a re d to
H e a rt -A lo n e T ra n s p la n ts * (T ra n s p la n ts : 1 /1 9 8 2 -6 /2 0 0 3 )
0
2 0
4 0
6 0
8 0
1 0 0
0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2
Ye a rs f ro m K id ne y T ran s p la n t R e p o rt fo r K id n e y a fte r He ar t T ra n sp la n ts a n d Yea rs from T ra n s p la n t + M e d ia n for He a rt -A lo n e T ra n s p la n ts **
Su
rviv
al (
%)
.
He a r t a lo n e (N =1 2 ,8 6 7 ) K id n e y a f te r He a r t (N = 4 9 9 )
H ALF -L IFE F O LL O W IN G K ID N E Y T R AN S P LAN T ( K I AFT E R H R ) O R FR O M M E D IAN T IM E T O K ID N E Y T R AN S P L AN T R E P O R T (H E AR T AL O N E ):H e art alon e * = 7.4 Y e arsK id ne y aft e r H e a rt = 4 .9 Y e a rs
IS H L T 2005
* F o r c o m p a riso n p u rp o se s , th e h e a rt-a lo n e tra n sp la n t c o h o rt w a s lim ite d to th o se tra n sp la n ts th a t h a d s u r v ive d to th e m e d ia n tim e to k id n e y tra n sp la n t fo r th e k id n e y a f te r h e a rt tra n sp la n t (8 .0 y e a rs).
* * S u r v iva l t im e s in c e “ k id n e y tra n sp la n t” (tra n sp la n t d a te n o t re p o rte d , o n ly t im e p o in t a t w h ic h k id n e y tra n sp la n t h a s a lre a d y o c c u rre d )
J H e a rt L u n g T ra n s p la n t 2 0 0 5 ;2 4 : 9 4 5 -9 8 2 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 FactorsCellular Rejection scoreAntibody –mediated rejectionBalance of Immunosuppression
SMC EC
NonImmune factorsMode of Brain DeathIschemia Reperfusion injuryHyperlipidemiaHypertensionCMV infectionDonor age
Denudinginjury
Nondenudinginjury
PDGF, FGF, IGFTGF-ß, TNF, IL-1
MHC-IIICAM,VCAM
IL-1, IL-2, IL-6, TNFPDGF, FGF, IGF, TGF-ß
Platelets
T-lymphocyte
Macrophage
selectins
INFLAMMATION
Mehra MR. AJT 2006 (in press)
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Maximal Intimal Thickening Predicts Cardiac Events
Intimal thickening (mm)
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.
0.35 0.50 1.000
Early
Mid
Late
Normal
SevereAbnormal
LowHighModerate
Risk of cardiac event
Post-transplant
time
“Prognostically relevant”- High plaque burden- Link with cardiac events
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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 44
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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
0
25
50
75
100H
uH
-7
HE
PG
2
SW
480
SW
620
HT
-29
Lo
Vo
Jurk
at
TH
P-1
HU
VE
C
CsA Sirolimus MPA Leflunomide
Gro
wth
inh
ibit
ion
(%
)
Hepatic cancer Colorectal cancer Myelodysplasia
Casadio F. Transplant Proc 2005; 37:2144.
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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 CenterUniversity of Maryland School of Medicine
• Sarah Miller
Project Coordinator Scientific Registry of Transplant Recipients (SRTR) University of Michigan