Predicting Cardiac Allograft Vasculopathy Using Circulating Vascular Endothelial Growth Factor in Pediatric Heart Transplant Recipients

Predicting Cardiac Allograft Vasculopathy Using Circulating Vascular Endothelial Growth Factor in Pediatric Heart Transplant Recipients

S78 The Journal of Heart and Lung Transplantation, Vol 36, No 4S, April 2017 1( 82) 1( 83) Impact of Newly Detected Donor Specific Anti-HLA Antib...

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The Journal of Heart and Lung Transplantation, Vol 36, No 4S, April 2017

1( 82)

1( 83)

Impact of Newly Detected Donor Specific Anti-HLA Antibody in the First Year After Pediatric Heart Transplantation A.I. Dipchand ,1 S. Webber,2 K. Much,3 B. Feingold,4 C. Bentlejewski,5 E.D. Blume,6 R. Shaddy,7 C. Canter,8 J. Lamour,9 W. Mahle,10 W. Zuckerman,11 H. Diop,12 Y. Morrison,13 B. Armstrong,3 D. Ikle,3 J. Odim,13 A. Zeevi,14  T. CTOTC-04 Investigators13. 1Hosp for Sick Children, Toronto, ON, Canada; 2Vanderbilt Univ, Nashville, TN; 3Rho, Chapel Hill, NC; 4Children's Hospital of Pittsburgh, Pittsburgh, PA, Canada; 5Children's Hospital of Pittsburgh, Pittsburgh, PA; 6Children's Hospital Boston, Boston, MA, Canada; 7Children's Hospital of Philadelphia, Philadelphia, PA; 8St Louis Children's Hospital, St Louis, MO; 9Montefiore Children's Hospital, New York, NY; 10Children's Healthcare of Atlanta, Atlanta, GA; 11Children's Hospital of New York, New York, NY; 12NIAID, Bethesda, MD, Canada; 13NIAID, Bethesda, MD; 14Univ of Pittsburgh, Pittsburgh, PA.

HLA Eplet Mismatching Is Associated with Increased Risk of Graft Loss in Pediatric Heart Transplant Recipients E. Albers ,1 N. Jorgensen,2 J. Friedland-Little,1 B. Hong,1 M. Kemna,1 P. Warner,3 Y. Law.1  1Seattle Children's Hospital, Seattle, WA; 2University of Washington, Seattle, WA; 3Bloodworks Northwest, Seattle, WA.

Purpose: Post-transplant de novo anti-HLA donor specific antibodies (DSA) indicate a worse outcome in adult transplantation. No large prospective studies have established the prevalence of newly detected DSA after pediatric heart transplant (HT), nor studied their impact on outcomes. We used the CTOTC-04 cohort to determine the incidence, specificity and time course of newly detected DSA in the 1st yr post-HT. Methods: Prospectively recruited consecutive pts (age < 21 y) listed for HT at 8 centers were categorized by sensitization status as non-sensitized or sensitized (pre-HT positive Luminex® screen with ≥ 1 anti-HLA Ab at ≥ 1000 MFI confirmed by single antigen bead testing). Immunosuppression was standardized and a core antibody lab was used. Pts were categorized by the absence/presence and timing (Early: 6-42 d, Late: ≥ 42 d) of newly detected DSA (≥ 1000 MFI) in the 1st yr post-HT. Results: From 2/2011 - 12/2013, 240 received HT of which 237 (122 sensitized) had pre-HT samples. There were 1599 total 1st yr post-HT samples screened for DSA. Median age at HT was 6 y (1 m - 20 y) with 53% males and 44% CHD. One hundred and fifty-nine (67%) had no newly detected DSA in the 1st yr, while 61 (26%) had Early and 17 (7%) had only Late DSA. Pt characteristics and DSA profiles are in the Table. Among 186 pts without detectable DSA at HT, freedom from rejection at 1 yr in the No DSA postHT, Early and Late DSA groups were: AMR (96.1, 89.6, 92.9%; p= 0.24), ACR (86.4, 57.5, 64.3 %; p< 0.01), and rejection with HC (99.2, 91.7, 92.3%; p= 0.03) respectively (only 4 pts had rejection with HC). Conclusion: Most recipients did not develop DSA within the 1st yr post-HT. When present, it was mostly detected early suggesting that memory responses (or potentially passive transmission) predominate over true de novo DSA production. Patients without new post-HT DSA had the highest freedom from all forms of rejection, which was significant for ACR. Late outcomes of 1st yr DSA are being studied in an extended cohort of 336 pts within the CTOT-C consortium.

Early vs Late vs No Newly Detected DSA Development

No newly detected DSA n= 159 (67%)

Late Early DSA     n= 61 DSA     n= 17 (26%) (7%)

Age at HT (yrs)

6.0 (0.1-21.0)

8.8 (0.3-21.0)

5.2 (0.4-19.1)

Male sex (%)

82 (52)

37 (61)

7 (41)

Diagnosis CHD (%)

63 (40)

37 (61)

5 (29)

PreTx Ab status Non-sensitized (n= 115)

88 (55%)

21 (34%)

6 (35%)

Sensitized, no DSA (n= 71)

45 (28%)

18 (30%)

8 (47%)

Sensitized, DSA (n= 51)

26 (17%)

22 (36%)

3 (18%)

Time to newly detected DSA development (days)

10 (6-39)

162 (45-355)

Maximum MFI

5100 (1000-22400)

2800 (1100-19100)

Class I only (%)

23 (38)

7 (41)

Class II only (%)

12 (20)

6 (35)

Class I and Class II (%)

26 (43)

4 (24)

Purpose: Mismatching between donor and recipient human leukocyte antigen (HLA) alleles has been associated with increased graft loss in pediatric heart recipients. However, many recipients with a high degree of HLA allele mismatch do well, without rejection or early graft loss. The antigenicity of each HLA molecule is determined by surface amino acid residues, termed eplets, which can vary even among the same allele designation. We hypothesized that molecular-level HLA eplet mismatching is a better predictor of graft loss in pediatric heart recipients than standard allele matching alone. Methods: A retrospective review of the Pediatric Heart Transplant Study database identified pediatric heart recipients (< 18yo at listing) with complete donor and recipient HLA typing (A, B, and DR). HLAMatchmaker software was used to determine the number of class-specific eplet mismatches between each donor-recipient pair. Multivariable Cox regression analysis was used to examine associations between allele or eplet mismatching and graft loss. Results: 2479 recipients met inclusion criteria. The majority had > 3 allele mismatches (2183, 88%) or > 20 eplet mismatches (1909, 77%). Classspecific analysis showed that neither HLA-I (A and B) nor HLA-II (DR) allele mismatching was significantly associated with graft loss. However, recipients with 10 or more HLA-I eplet mismatches were at significantly increased risk for graft loss compared to those with < 10 HLA-I eplet mismatches (10-20 mismatches: HR 1.34, CI 1.02-1.77, p= 0.038; > 20 mismatches: HR 1.47, CI 1.02-2.1, p= 0.036). HLA-II eplet mismatching was not associated with graft loss. Conclusion: Higher degree of HLA-I eplet mismatching is associated with increased risk of graft loss in this cohort of pediatric heart recipients. Conversely, neither HLA-I nor HLA-II allele mismatching was significantly associated with graft loss. Eplet mismatch analysis may provide more accurate prediction of risk for post-transplant graft loss than allele matching alone, and further study is warranted. 1( 84) Predicting Cardiac Allograft Vasculopathy Using Circulating Vascular Endothelial Growth Factor in Pediatric Heart Transplant Recipients K. Watanabe , S.D. Miyamoto, S.J. Nakano.  School of Medicine, University of Colorado Denver, Aurora, CO. Purpose: Increases in serum Vascular Endothelial Growth Factor (VEGF) will assist in risk-stratification of pediatric heart transplant recipients by predicting the development of cardiac allograft vasculopathy (CAV). Methods: Serum samples were obtained from pediatric (< 18 years) heart transplant recipients at the Children’s Hospital of Colorado. Samples were obtained at the time of new CAV, diagnosed by intravascular ultrasound (IVUS) and/or angiography. Serum from the same subject prior to the diagnosis of CAV was also evaluated. Control samples are from pediatric heart transplant recipients of similar age and number of years post-transplant. Samples were excluded if there was concurrent biopsy-proven rejection. VEGF-A was quantified in serum samples using the Human VEGF Quantikine ELISA Kit (R&D Systems). A comparison between the control, pre-CAV, and CAV groups was made using analysis of variance (ANOVA) testing with a HolmSidak’s multiple comparisons test. Receiver operator curve (ROC) analysis was used to determine positive predictive value, assuming a CAV prevalence of 35% at 10 years post-transplant. Results: The control and CAV groups do not differ significantly with respect to sex, median age at transplant, age at the time of serum collection, or time from transplant to serum collection; the median time between pre-CAV and CAV blood draws is 22 months. Serum VEGF levels in both the pre-CAV (n= 28) and CAV (n= 25) groups are significantly higher than in controls (n= 15, p= 0.0009 and p= 0.011 respectively). Furthermore, relative VEGF levels are similar between pre-CAV and CAV groups. A relative VEGF of 1.071 gives sensitivity of 90%, specificity of 67%, and a positive predictive value of 60%.

Abstracts S79 1( 86) Donor-Derived Transmission of Hepatitis C in a Hepatitis C-Naïve Heart Transplant Recipient Treated with a Pan-Genotypic Agent: Viral Kinetics and Implications for Expanded Donor Availability T. Sam ,1 S. Wada,2 S.M. Joseph,3 J.F. Trotter,1 S.K. Asrani,1 B. Lima,3 G. Gonzalez-Stawinski,3 S.A. Hall,3 R.L. Gottlieb.3  1Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Dallas, TX; 2Transplant Infectious Diseases, Baylor University Medical Center, Dallas, Dallas, TX; 3Baylor Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Dallas, TX.

Conclusion: Serum VEGF levels are elevated in pediatric heart transplant recipients prior to IVUS-based and angiographic diagnoses of CAV and may serve as a pathophysiologically relevant biomarker for early CAV detection and risk-stratification. 1( 85) Continuous VAD Placement in Young Pediatric Patient with Fontan Physiology D.S. Burstein ,1 D. Nandi,2 J.W. Gaynor,1 J.W. Rossano.1  1Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA; 2Pediatric Cardiology, Nationwide Children's Hospital, Columbus, OH. Introduction: The use of ventricular assistance devices (VADs) in patients with failing Fontan physiology is an emerging approach for mechanical support. However, due to size limitations and risk for device inflow obstruction, continuous flow devices have not previously been used in young single ventricle patients with BSA less than 0.7 m2. Here, we describe the first case of continuous centrifugal-flow HeartWare VAD in a young child with a failing single ventricle using a novel surgical approach of atrial cannulation and tricuspid valve excision. Case Report: A three-year-old, 15 kg female (BSA 0.61 m2) with double outlet right ventricle and mitral atresia status post Fontan palliation and unsuccessful tricuspid valvuloplasty underwent prosthetic tricuspid valve replacement. Due to acutely increased afterload associated with prosthetic valve placement, her post-operative course was complicated by severe heart failure with resultant ventricular dilation and progressive para-valvar leak. She was listed for cardiac transplant and as a bridge to transplant, she underwent placement of a continuous, centrifugal-flow HeartWare VAD. Due to small patient size, right atrial venous cannulation was performed and the tricuspid valve was excised (see Figure). VAD settings were set at 2560 RPM with flows of 2.6-3 L/min. She successfully recovered from decompensated heart failure, and she continues on VAD support six months later without need for pump replacement. Summary: This is the first report of continuous centrifugal-flow VAD placement in a small child with Fontan physiology using atrioventricular valve excision. This has since become our institutional standard of practice for VAD support in young patients with single ventricle physiology.

Introduction: Hepatitis C virus (HCV) nucleic acid test (NAT) positive cardiac donors are rarely utilized given increased morbidity and mortality risk after orthotopic heart transplantation (OHTx). However, impact of highly effective HCV antivirals on donor-derived HCV outcomes remain unclear. We report successful transplantation with a high risk HCV NAT-positive donor into a HCV antibody negative OHTx recipient, and a sustained virologic response at 1 month of anti-HCV therapy. Case Report: An adult female heart transplant candidate with biventricular heart failure on two inotropes and not considered a candidate for bridging mechanical support therapy opted to accept a donor offer from a CDC highrisk, HCV NAT-positive donor. Immunosuppression included basiliximab induction, high-dose steroids, tacrolimus, and (per institutional protocol for CMV D+/R- mismatch) azathioprine. Upon a daily logarithmic rise in HCV viral load (graph) and adequate titers to ensure successful genotyping, once daily sofosbuvir 400 mg / velpatasvir 100 mg (Epclusa) was initiated in absence of data on HCV genotype. Initiation of therapy led to prompt and sustained decline in HCV viral load. HCV genotype 3a was confirmed after initiation of HCV therapy. HCV viral load remained negative at 1 month of therapy. Summary: We provide the first report of viral kinetics of donor-derived transmission of hepatitis C in a hepatitis C-naïve OHTx recipient treated with a novel pan-genotypic agent. The medical feasibility of early versus late treatment of HCV remains to be determined. The availability of effective pan-genotypic therapy for HCV has the potential to usher in a new era of expanded donor availability. Pharmacoeconomics remain the greatest limitation to wide availability of this promising tool to immediately expand donor availability for the sickest patients.

1( 87) Successful Remote Monitoring of Left Ventricular Assist Device Patients Using a Mobile Heart Failure Application R.J. Cogswell ,1 T.B. Freitag,1 C.A. Lilla,2 R. John.3  1Cardiology, University of Minnesota, Minneapolis, MN; 2Nursing, Fairview - University of Minnesota Medical Center, Minneapolis, MN; 3Cardiovascular Surgery, University of Minnesota, Minneapolis, MN. Introduction: Remote monitoring of heart failure (HF) patients is becoming increasingly common and has been associated with reduced heart failure readmissions. Use of this technology in the left ventricular assist device (LVAD) population has been minimally described. OnTrack is a mobile HF application developed to improve patient adherence, allow tracking of clinical parameters, and to facilitate communication between patients and care providers. We partnered with OnTrack to expand their platform to include the