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

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SW

62

0

HT

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Lo

Vo

Ju

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TH

P-1

HU

VE

C

CsA Sirolimus MPA Leflunomide

Gro

wth

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(%

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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