PEDIATRIC CARDIOLOGY
Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation
Scott R. Auerbach, MD*,
Cedric Manlhiot, BS ,
Sushma Reddy, MD*,
Caroline Kinnear, MS*,
Marc E. Richmond, MD*,
Dorota Gruber, MS*,
Brian W. McCrindle, MD, MPH,
Liyong Deng, MS ,
Jonathan M. Chen, MD ,
Linda J. Addonizio, MD*,
Wendy K. Chung, MD and
Seema Mital, MD,*
* Department of Pediatric Cardiology, Columbia University, Morgan Stanley Children's Hospital of New York–Presbyterian, New York, New York
Department of Pediatric Cardiac Surgery, Columbia University, Morgan Stanley Children's Hospital of New York-Presbyterian, New York, New York
Department of Genetics, Columbia University, Morgan Stanley Children's Hospital of New York-Presbyterian, New York, New York
Department of Pediatrics, Division of Cardiology, Labatt Family Heart Centre, University of Toronto, The Hospital For Sick Children, Toronto, Ontario, Canada
Manuscript received November 17, 2008;
revised manuscript received February 13, 2009,
accepted February 19, 2009.
* Reprint requests and correspondence: Dr. Seema Mital, Division of Cardiology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada (Email: seema.mital{at}sickkids.ca).
This work was presented in part at the American Academy of Pediatrics National Conference and Exhibition, October 26, 2007, and American Heart Association Annual Meeting, November 5, 2007.
Objectives: This study sought to investigate the influence of recipient renin-angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation.
Background: The RAAS influences cardiac function and up-regulates inflammatory/immune pathways. Little is known about the effect of recipient RAAS polymorphisms in pediatric cardiac transplantation.
Methods: Patients <25 years of age, after cardiac transplantation, were enrolled (2003 to 2008) and genotyped for polymorphisms in genes associated with RAAS upregulation: AGT-G, ACE-D, AGTR1-C, CYP11B2-G, and CMA-A. Presence of at least 1 high-risk allele was defined as a high-risk genotype. Univariable and multivariable associations between genotypes and outcomes were assessed in time-dependent models using survival, logistic, or linear regression models. Biopsy samples were immunostained for interleukin (IL)-6, transforming growth factor (TGF)-β, and tumor necrosis factor (TNF)- during rejection and quiescence.
Results: A total of 145 patients were studied, 103 primary cohort and 42 replication cohort; 81% had rejection, 51% had graft dysfunction, and 13% had vasculopathy, 7% died and 8% underwent re-transplantation. A higher number of homozygous high-risk RAAS genotypes was associated with a higher risk of graft dysfunction (hazard ratio [HR]: 1.5, p = 0.02) and a higher probability of death (HR: 2.5, p = 0.04). The number of heterozygous high-risk RAAS genotypes was associated with frequency of rejection (+0.096 events/year, p < 0.001) and rejection-associated graft dysfunction (+0.37 events/year, p = 0.002). IL-6 and TGF-β were markedly upregulated during rejection in patients with  2 high-risk RAAS genotypes.
Conclusions: Recipient RAAS polymorphisms are associated with a higher risk of rejection, graft cytokine expression, graft dysfunction, and a higher mortality after cardiac transplantation. This may have implications for use of RAAS inhibitors in high-risk patients after transplantation.
Key Words: cardiac transplantation • polymorphism • genetics • angiotensin • cytokines
|
Abbreviations and Acronyms
| | ACE
= angiotensin-converting enzyme | | AGT
= angiotensinogen M235T | | AGTR1
= angiotensin II type 1 receptor | | CI = confidence interval | | CMA
= cardiac chymase A | | CYP11B2
= aldosterone synthase | | HR = hazard ratio | | IL = interleukin | | RAAS = renin-angiotensin-aldosterone system | | TGF = transforming growth factor | | TNF = tumor necrosis factor |
|
Related Article
-
Inside This Issue
J. Am. Coll. Cardiol. 2009 53: A28.
[Full Text]
[PDF]
|
