1. Graft Dysfunction after Heart Transplantation
Joseph W. Rossano, M.D., F.A.A.P., F.A.C.C.
Medical Director, Heart Failure & Transplantation
Interim Director, Cardiac Intensive Care Unit
The Children’s Hospital of Philadelphia
University of Pennsylvania

2. Disclosures
No relevant financial disclosures

3. Response from Fellows when I Lecture on Heart Transplant

4. Take-home Points Graft failure after transplant is not rare
Early (primary graft failure)
Midterm (acute rejection)
Late (cardiac allograft vasculopathy)
High mortality rate
Treatment
Standard acute heart failure management
Often augmentation of immunosuppression
Early use of mechanical support

5. Death After Transplant
Primary graft failure
Acute rejection
Cellular rejection
Antibody mediated rejection (humoral rejection)
Cardiac allograft vasculopathy
Infection
Malignancy

6. Death After Transplant
Primary graft failure
Acute rejection
Cellular rejection
Antibody mediated rejection (humoral rejection)
Cardiac allograft vasculopathy
Infection
Malignancy

7. Risks Change Over Time

8. Primary Graft Failure (PGF)
Graft failure and circulatory collapse that occurs within 24 hours of transplant
Immunologic factors
Pre-formed antibodies against donor antigents (sensitized patient)
Positive crossmatch
Non-immunologic factors
Patient factors
Donor factors
Operative factors

9. Pre-Formed Antibodies
Antibodies directed at major histocompatibility complex (MHC) class I or class II human leukocyte antigens (HLA)
Recipients with anti-HLA antibodies are sensitized
Acute graft failure (hyperacute rejection)
Antibody mediated rejection
Cardiac allograft vasculopathy

10. Outcome of Crossmatch
The presence of preformed cytotoxic antibodies against the donor appears to be a strong contraindication to transplantation
Patel R, et al. NEJM. 1969

11. Dealing With Antibodies
Avoid donors with possibility of a positive crossmatch
Prospective vs virtual crossmatch
Desensitize recipient
Transplant expecting a positive crossmatch
Remove antibodies
Enhance immunosuppression

12. Sensitized Patients
Rossano JW, et al. JTCVS. 2010

13. Non-Immunologic Risk Factors for PGF
Congenital heart disease
Multiple reoperations
Comorbidities
Liver disease, renal dysfunction
Ventilator dependent
Elevated PVR
Retransplant
Kobashigawa, et al. JHLT 2014

14. Every Patient Listed for Transplant at CHOP
Congenital heart disease
Multiple reoperations
Comorbidities
Liver disease, renal dysfunction
Ventilator dependent
Elevated PVR
Retransplant

15. Pre-operative Condition Matters
Almond CS, et al. AJT. 2012

16. Treatment of Primary Graft Failure
Inotropic support
iNO
Enhanced immunosuppression
If a positive crossmatch
Steroids
T-cell cytolytic therapy (e.g. ATG)
Plasmapheresis
B-cell therapies
Anti-CD20 antibodies (Rituximab)
Proteasome inhibitors (Bortezomib)

17. Mechanical Support for PGF
Overall high mortality rate
~30% - 50%
Better outcomes with isolated RV failure compared to isolated LV failure or biventricular failure
RV adapts to higher PVR
Move to mechanical support prior to severe end-organ dysfunction
Huang J, et al. JHLT. 2004; Tissot C, et al. JACC. 2009

18. Outcomes of PGF
Carmena MD, et al. JHLT. 2013

19. Acute Cellular Rejection ISHLT 1R Rejection

20. ISHLT 2R Rejection

21. Grade 3R Rejection

22. Antibody Mediated Rejection (AMR)

23. Treating Acute Cellular Rejection
Low grade rejection
Patient usually asymptomatic
Graft functioning fairly well
First line treatment steroids
Goal is to treat low-grade rejection to prevent high grade rejection / graft dysfunction or loss
High grade rejection
Hemodynamic compromise common
Higher likelihood of premature graft loss
Treatment more involved

24. Treatment of AMR No standard treatment agreed upon Plasmaphresis IVIG
Rituximab
Other immunosuppression

25. VAD Support for Rejection
Morales DL, et al. ASAIO 2007

26. Cardiac Allograft Vasculopathy (CAV)
Occurs uniquely in transplant patients
Rapidly progressive atherosclerosis
Intimal proliferation in early stages
Luminal stenosis, occlusion, and infarction
Sudden death may be first clinical manifestation
Immunologic and non-immunologic mechanism involved
Major limitation of long-term survival

27. CAV

28. Risk Factors for CAV

29. IVUS and CAV

30. Effective Therapies for CAV
Steroids
T-cell cytolytic therapy
Plasmapheresis
Antivirals
CABG or PTCA / Stents
Re-transplantation

31. Effective Therapies for CAV
Steroids
T-cell cytolytic therapy
Plasmapheresis
Antivirals
CABG or PTCA / Stents
Re-transplantation

32. Prevention of CAV: Everolimus
Eisen HJ, et al. NEJM 2003

33. Outcomes after CAV Diagnosis
Pahl E, et al. JHLT. 2005

34. Mechanical Support for CAV
Limited data do guide decisions
VADs have been utilized
Biventricular support often needed
Worse post-transplant outcomes on patients bridged with VADs
Potential role for TAH
Stop all immunosuppression
Successful cases reported
Limited experience

35. Summary Graft failure after transplant is not rare High mortality rate
Early (primary graft failure)
Midterm (acute rejection)
Late (cardiac allograft vasculopathy)
High mortality rate
Treatment
Standard acute heart failure management
Often augmentation of immunosuppression
Early use of mechanical support

36. Thank you for your attention.

37. Wait List Mortality

38. Factors Associated with Survival
ECMO
Renal failure
Respiratory failure
Hyperbilirubinemia

39. Sensitized Patients
Rossano JW, et al. JTCVS. 2010

40. Kaplan-Meier Plot for Graft Survival Post-HTx
Years from Transplant
Group 4: T-/B-cell XM-
Group 1: T-/B-cell CDC-XM+
Group 2: T-/B-cell FC-XM+
Group 3: B-cell FC-XM+
Group 1 vs. Group 4: p<0.001
Group 1 vs. Group 2: p=0.046
Group 1 vs. Group 3: p=0.003
Group 2 vs. Group 4: p=0.115
Group 3 vs. Group 4: p=0.297
Group 2 vs. Group 3: p=0.598
Keeshan B, et al. ISHLT 2014

41. Factors Associated with PRAs in Pediatric Patients
Characteristic
No PRA
(n=2711)
PRA 1-10%
(n=436)
PRA >10%
(n=387)
P Value
Age, years
6.2 ± 6.3
6.6 ± 6.2
7.1 ± 6.2
0.043
CHD
47%
44%
52%
< 0.001
Inotropic support
32%
31%
41%
0.003
Wait list time, months
2.3 ± 4.6
2.5 ± 5.7
3.5 ± 5.8
0.006
Year of transplant
79%
14% 7%
75%
10%
15%
Rossano JW, et al. JTCVS. 2010