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Compassionate Allowances Outreach Compassionate Allowances Outreach Hearing on Cardiovascular Disease and Hearing on Cardiovascular Disease and
Multiple Organ TransplantsMultiple Organ Transplants
Compassionate Allowances Outreach Compassionate Allowances Outreach Hearing on Cardiovascular Disease and Hearing on Cardiovascular Disease and
Multiple Organ TransplantsMultiple Organ Transplants
Clive O. Callender, M.D., FACSNovember 9, 2010
Clive O. Callender, M.D., FACSNovember 9, 2010
Howard University Hospital Howard University Hospital Transplantation ServicesTransplantation Services“Heart Transplantation”“Heart Transplantation”
Howard University Hospital Howard University Hospital Transplantation ServicesTransplantation Services“Heart Transplantation”“Heart Transplantation”
El Centro de Transplantes de El Centro de Transplantes de Howard University HospitalHoward University Hospital
El Centro de Transplantes de El Centro de Transplantes de Howard University HospitalHoward University Hospital
In 1973, Dr. Callender developed the first minority oriented transplant center in this country.
In 1973, Dr. Callender developed the first minority oriented transplant center in this country.
National Minority Organ Tissue Transplant Education National Minority Organ Tissue Transplant Education Program Founder (MOTTEP®)Program Founder (MOTTEP®)
Waiting list candidatesWaiting list candidates 109,100 as of 109,100 as of today 4:24pm today 4:24pm
Waiting list candidatesWaiting list candidates 109,100 as of 109,100 as of today 4:24pm today 4:24pm
ObjectiveObjectiveObjectiveObjective
• Current Status of Heart Transplantation
• Current Status of Heart Transplantation
Growth in Number of Transplanted Organs
Source: 2005 OPTN/SRTR
Growth in Number of Transplanted Organs
Source: 2005 OPTN/SRTR • Organs End of Year Percent Change• 2003 2004 • Total 25,083 26,539 5.8%
• Kidney 14,856 15,671 5.5% – Deceased donor 8,388 9,025 7.6% – Living donor 6,468 6,646 2.8%
• PTA 117 132 12.8% • PAK 343 418 21.9% • Kidney-pancreas 868 879 1.3%
• Liver 5,364 5,780 7.8% – Deceased donor 5,043 5,457 8.2% – Living donor 321 323 0.6%
• Intestine 52 52 0.0% • Heart 2,026 1,961 -3.2% • Lung 1,080 1,168 8.1% •• Heart-lung 28 37 32.1%
• Organs End of Year Percent Change• 2003 2004 • Total 25,083 26,539 5.8%
• Kidney 14,856 15,671 5.5% – Deceased donor 8,388 9,025 7.6% – Living donor 6,468 6,646 2.8%
• PTA 117 132 12.8% • PAK 343 418 21.9% • Kidney-pancreas 868 879 1.3%
• Liver 5,364 5,780 7.8% – Deceased donor 5,043 5,457 8.2% – Living donor 321 323 0.6%
• Intestine 52 52 0.0% • Heart 2,026 1,961 -3.2% • Lung 1,080 1,168 8.1% •• Heart-lung 28 37 32.1%
No of Transplanted Organs vs Waiting List 2004No of Transplanted Organs vs Waiting List 2004No of Transplanted Organs vs Waiting List 2004No of Transplanted Organs vs Waiting List 2004
Recovered Transplanted Waiting List
• Total 25,237 26,539 86,378
• Kidney 12,575 15,671 (9,025) 57,910• PTA 2,021 132 504• PAK 418 973• K-P 879 2,410• Liver 6,405 5,780 (5,457) 17,133• Intestine 167 52 196• Heart 2,096 1,961 3,237• Lung 1,973 1,168 3,852• Heart-lung 37 171• Source: 2005 OPTN/SRTR Annual Report,
Recovered Transplanted Waiting List
• Total 25,237 26,539 86,378
• Kidney 12,575 15,671 (9,025) 57,910• PTA 2,021 132 504• PAK 418 973• K-P 879 2,410• Liver 6,405 5,780 (5,457) 17,133• Intestine 167 52 196• Heart 2,096 1,961 3,237• Lung 1,973 1,168 3,852• Heart-lung 37 171• Source: 2005 OPTN/SRTR Annual Report,
Graft SurvivalGraft SurvivalGraft SurvivalGraft Survival
Follow-up Period 1 Year 10 Years Tx 2002-2003 Tx 1993-2003
Kidney Deceased Donor • Graft Survival 89.0% 40.5% • Patient Survival 94.6% 60.7% Kidney: Living Donor • Graft Survival 95.1% 56.4% • Patient Survival 97.9% 76.4% Kidney-Pancreas Kidney Graft Survival 91.7% 52.5% Pancreas Graft Survival 85.8% 53.6% Liver Deceased Donor• Graft Survival 82.2% 52.5% • Patient Survival 81.7% 67.0% Intestine Graft Survival 73.8% 22.0% Heart Graft Survival 86.8% 51.1% Lung Graft Survival 81.4% 22.1% Heart-Lung Graft Survival 55.8% 24.6%
Follow-up Period 1 Year 10 Years Tx 2002-2003 Tx 1993-2003
Kidney Deceased Donor • Graft Survival 89.0% 40.5% • Patient Survival 94.6% 60.7% Kidney: Living Donor • Graft Survival 95.1% 56.4% • Patient Survival 97.9% 76.4% Kidney-Pancreas Kidney Graft Survival 91.7% 52.5% Pancreas Graft Survival 85.8% 53.6% Liver Deceased Donor• Graft Survival 82.2% 52.5% • Patient Survival 81.7% 67.0% Intestine Graft Survival 73.8% 22.0% Heart Graft Survival 86.8% 51.1% Lung Graft Survival 81.4% 22.1% Heart-Lung Graft Survival 55.8% 24.6%
UNOS/SRTR, 2003
The History Of Heart The History Of Heart TransplantationTransplantation
The History Of Heart The History Of Heart TransplantationTransplantation
3rd December 1967
Nearly 40 years and 70,000 transplants
Orthotopic ImplantationOrthotopic ImplantationOrthotopic ImplantationOrthotopic Implantation
• Positioning of donor heart
• Creation of left atrial anastomosis
• Positioning of donor heart
• Creation of left atrial anastomosis
Orthotopic Orthotopic ImplantationImplantationOrthotopic Orthotopic ImplantationImplantation
• Completion of right atrial anastomosis (standard technique)
• Completion of right atrial anastomosis (standard technique)
• Aortic anastomosis
• Pulmonary artery anastomosis
• Aortic anastomosis
• Pulmonary artery anastomosis
Orthotopic Orthotopic ImplantationImplantation
Orthotopic Orthotopic ImplantationImplantation• Completed
transplant• Pacing wires
on donor portion of right atrium and ventricle
• Pericardium left open
• Completed transplant
• Pacing wires on donor portion of right atrium and ventricle
• Pericardium left open
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 15
ISHLT/UNOS Registry ISHLT/UNOS Registry DatabaseDatabase
Number of Transplants PerformedNumber of Transplants Performed
ISHLT/UNOS Registry ISHLT/UNOS Registry DatabaseDatabase
Number of Transplants PerformedNumber of Transplants Performed
ISHLT 2003J Heart Lung Transplant 2003; 22: 610-72.
Organ Transplants reported through 2001
Heart 61,533
Heart-Lung
2,935
Lung 14,588
Current Trends In Transplant Current Trends In Transplant CandidacyCandidacy
Current Trends In Transplant Current Trends In Transplant CandidacyCandidacy
• 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
• 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.
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 18
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 19
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 20
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 21
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 22
Heart TransplantationHeart TransplantationHeart TransplantationHeart 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)
• 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)
Immunosuppression Immunosuppression Management During Management During Maintenance PhaseMaintenance Phase
Immunosuppression Immunosuppression Management During Management During Maintenance PhaseMaintenance Phase
Low Breakthrough rejection
High Infections Malignancies
Therapeutic
Nephrotoxicity
HypertensionDiabetes
Neurotoxicity
30 - 40%30 - 55%5 - 10%
10 - 30%
Common Immunosuppressive Common Immunosuppressive Regimen Regimen
in 2005in 2005
Common Immunosuppressive Common Immunosuppressive Regimen Regimen
in 2005in 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)
• 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)
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 Trends in Maintenance Immunosuppression Prior to Discharge for Heart Transplantation, 1995-2004Discharge for Heart Transplantation, 1995-2004
Trends in Maintenance Immunosuppression Prior to Trends in Maintenance Immunosuppression Prior to Discharge for Heart Transplantation, 1995-2004Discharge for Heart Transplantation, 1995-2004
Major Post Transplant Major Post Transplant ComplicationsComplications
Major Post Transplant Major Post Transplant ComplicationsComplications
• Rejection• Infection• Cardiac allograft vasculopathy (CAV)• Hypertension• Nephrotoxicity• Malignancy
• Rejection• Infection• Cardiac allograft vasculopathy (CAV)• Hypertension• Nephrotoxicity• Malignancy
RejectionRejectionRejectionRejection• 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
• 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
R = RevisedStewart S, et al. JHLT 2005 in press
Treatment required
Acute Cellular RejectionAcute Cellular RejectionAcute Cellular RejectionAcute Cellular Rejection2004 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
Incidence of BPR in Randomized Heart Incidence of BPR in Randomized Heart Transplant Immunosuppression TrialsTransplant Immunosuppression Trials
Incidence of BPR in Randomized Heart Incidence of BPR in Randomized Heart Transplant Immunosuppression TrialsTransplant 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)
Treatment of RejectionTreatment of RejectionTreatment of RejectionTreatment 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
• 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
RejectionRejectionRejectionRejection
• 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
• 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
Specific Causes of Death One Specific Causes of Death One Year Year
After Cardiac TransplantationAfter Cardiac Transplantation
Specific Causes of Death One Specific Causes of Death One Year Year
After Cardiac TransplantationAfter 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
Long Term ChallengesLong Term ChallengesLong Term ChallengesLong Term Challenges
• Renal failure and metabolic adverse effects
• Cardiac allograft vasculopathy• Malignancy
• Renal failure and metabolic adverse effects
• Cardiac allograft vasculopathy• Malignancy
Post-Heart Transplant Morbidity For AdultsPost-Heart Transplant Morbidity For AdultsCumulative Incidence for Survivors (Apr,94 - Dec00)Cumulative Incidence for Survivors (Apr,94 - Dec00)
Post-Heart Transplant Morbidity For AdultsPost-Heart Transplant Morbidity For AdultsCumulative Incidence for Survivors (Apr,94 - Dec00)Cumulative Incidence for Survivors (Apr,94 - Dec00)
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
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
37
Renal Function in Renal Function in TransplantationTransplantation
Renal Function in Renal Function in TransplantationTransplantation
• 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
• 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
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 39
The Problem Of Cardiac The Problem Of Cardiac Allograft VasculopathyAllograft Vasculopathy
The Problem Of Cardiac The Problem Of Cardiac Allograft VasculopathyAllograft 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
• 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
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)
Maximal Intimal Thickening Maximal Intimal Thickening Predicts Predicts
Cardiac EventsCardiac Events
Maximal Intimal Thickening Maximal Intimal Thickening Predicts Predicts
Cardiac EventsCardiac 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
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 43
Areas of Current Uncertainty and Future Areas of Current Uncertainty and Future Research Regarding Malignancies in Heart Research Regarding Malignancies in Heart
TransplantationTransplantation
Areas of Current Uncertainty and Future Areas of Current Uncertainty and Future Research Regarding Malignancies in Heart Research Regarding Malignancies in Heart
TransplantationTransplantation
• 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
• 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.
Effects on Human Tumor Cell Effects on Human Tumor Cell GrowthGrowth
Effects on Human Tumor Cell Effects on Human Tumor Cell GrowthGrowth
0
25
50
75
100H
uH
-7
HE
PG
2
SW
48
0
SW
62
0
HT
-29
Lo
Vo
Ju
rka
t
TH
P-1
HU
VE
C
CsA Sirolimus MPA Leflunomide
0
25
50
75
100H
uH
-7
HE
PG
2
SW
48
0
SW
62
0
HT
-29
Lo
Vo
Ju
rka
t
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.
Heart Transplantation:Heart Transplantation:2005 and Beyond2005 and Beyond
Heart Transplantation:Heart Transplantation:2005 and Beyond2005 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
• 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