Current Status and Future Challenges in Heart Transplantation

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
(No Transcript)
4
(No Transcript)
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
Orthotopic Implantation

• Aortic anastomosis
• Pulmonary artery anastomosis

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
11
12
ISHLT/UNOS Registry DatabaseNumber of
Transplants Performed
Organ Transplants reported through 2001
Heart 61,533
Heart-Lung 2,935
Lung 14,588
ISHLT
2003
J Heart Lung Transplant 2003 22 610-72.
13
Current Trends In Transplant Candidacy

• Older patients, gt 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
14
15
15
16
16
17
17
18
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 Breakthrough rejection
High Infections Malignancies
Therapeutic NephrotoxicityHypertensionDiabetesNeurotoxicity 30 - 4030 - 555 - 1010 - 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
Trends in Maintenance Immunosuppression Prior to
Discharge for Heart Transplantation, 1995-2004
Source 2005 OPTN/SRTR Annual Report.
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
(No Transcript)
26
(No Transcript)
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 - Moderate A - Multifocal Multifocal infiltrate with myocyte damage
Multifocal B - Diffuse Diffuse infiltrate with myocyte damage
4 - Severe Diffuse polymorphous infiltrate with extensive myocyte damage edema hemorrhage vasculitis
28
GRADE 1A
GRADE 1B
Mild
GRADE 2
29
GRADE 3A
GRADE 3B
Threshold Mandatory For Therapy
GRADE 4
30
New Biopsy Grading Scale
31
Acute Cellular Rejection
Acute Cellular Rejection
2004 proposed grade 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
Treatment required
R Revised Stewart S, et al. JHLT 2005 in press
32
Incidence of BPR in Randomized Heart Transplant
Immunosuppression Trials
Trial 1st yearpublished 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 44p 0.046 (6 mo)
Neoral vs Sandimune (n 188 n 192) 1999 42.6 vs 41.7 p ns (6 mo)
33
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
CRTD 1990-1999, n 7290
Rejection Infection Non-specific graft
failure Neurologic Sudden
0.025
Malignancy
0.020
0.015
Allograft CAD
Deaths / year
0.010
0.005
0.000
7
1
3
4
6
8
9
10
2
5
Time after transplant (years)
Kirklin JK, et al. J Thorac Cardiovasc Surg 2003
125881-90.
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 gt 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
38
39
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 lt 0.001

Liver
Intestine
Lung
Cumulative incidence of CRF
Heart
Heart- lung
12
24
36
48
60
72
84
96
108
120
0
Time since transplantation (months)
Ojo AO et al. N Engl J Med 2003 349931-40.
40
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
(No Transcript)
43
Maximal Intimal Thickening Predicts Cardiac
Events
Prognostically relevant - High plaque burden -
Link with cardiac events
Intimal thickening (mm)
Mehra M et al. J Heart Lung Transplant 1995
14S207-11 Kobashigawa JA et al. J Am Coll
Cardiol 2005 451532-7 Tuzcu EM et al. J Am
Coll Cardiol 2005 451538-42.
44
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. 200524(8)1111-3.
46
Effects on Human Tumor Cell Growth
Growth inhibition ()
Hepatic cancer
Colorectal cancer
Myelodysplasia
Casadio F. Transplant Proc 2005 372144.
47
Heart Transplantation2005 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