1

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

2

The History Of Heart Transplantation

3rd December 1967

Nearly 40 years and 70,000 transplants

3

4

5

Chemical Structure of Cyclosporin-A

6

Orthotopic Implantation

• Positioning of donor heart

• Creation of left atrial anastomosis

7

Orthotopic Implantation

• Completion of right atrial anastomosis (standard tchnique)

8

• Aortic anastomosis

• Pulmonary artery anastomosis

Orthotopic Implantation

9

Orthotopic Implantation

• Completed transplant

• Pacing wires on donor portion of right atrium and ventricle

• Pericardium left open

10

Alternative Bicaval Approach

• Left atrial anastomosis performed

• Separate inferior and superior vena caval anastomosis

11

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

12

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

13

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.

14

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

15

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

16

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

17

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

18

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

19

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)

20

Immunosuppression Management During Maintenance Phase

Low Breakthrough rejection

High Infections Malignancies

Therapeutic

NephrotoxicityHypertension

DiabetesNeurotoxicity

30 - 40%30 - 55%5 - 10%

10 - 30%

21

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)

22

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

23

Major Post Transplant Complications

• Rejection

• Infection

• Cardiac allograft vasculopathy (CAV)

• Hypertension

• Nephrotoxicity

• Malignancy

24

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

25

26

27

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

28

GRADE 1A

GRADE 2

GRADE 1B

Mild

29GRADE 4

GRADE 3A GRADE 3B

ThresholdMandatory

ForTherapy

30

New Biopsy Grading Scale

31

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

32

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

34

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

35

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

36

Long Term Challenges

• Renal failure and metabolic adverse effects

• Cardiac allograft vasculopathy

• Malignancy

37

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

38

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

38

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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

40

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

41

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

42

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)

43

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

44

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

45

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.

46

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.

47

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

48

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