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ABSTRACT: OBJECTIVES: To assess the differences in rejection and infection complications between the most common contemporary immunosuppression regimen in pediatric heart transplantation (cytolytic induction, tacrolimus based) and classic triple-therapy (cyclosporine based without induction). STUDY DESIGN: We performed a retrospective, historical-control, observational study comparing outcomes in patients who underwent traditional immunosuppression (control group, n = 64) with those for whom the contemporary protocol was used (n = 39). Episodes of rejection, viremia (cytomegalovirus or Epstein-Barr virus), serious bacterial or fungal infections, anemia or neutropenia requiring treatment in the first year after heart transplantation, and 1-year survival were compared between traditional and contemporary immunosuppression groups. RESULTS: The 2 groups were similar with respect to baseline demographics. There were no differences in risk of cytomegalovirus, Epstein-Barr virus, or bacterial or fungal infections in the first year post-transplantation. Patients in the contemporary group were more likely to need therapy for anemia (51% vs 14%, P < .001) or neutropenia (10% vs 0%, P = .019). However, more contemporary protocol patients were rejection-free in the first year post-transplantation (63% vs 41%, P = .03). Overall graft survival was similar between groups (P = .15). CONCLUSIONS: A contemporary immunosuppression regimen using tacrolimus, mycophenolate mofetil, and induction was associated with less rejection in the first year, with no difference in the risk of infection but greater risk of anemia and neutropenia requiring treatment. Long-term follow-up on these patients will evaluate the impact of the immunosuppression regimen on survival.
The Journal of pediatrics 02/2013; · 4.02 Impact Factor
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ABSTRACT: OBJECTIVE: We hypothesized that isolated gastrointestinal complaints (abdominal pain, nausea, anorexia, weight loss), in the absence of other symptoms, were a common mode of initial presentation in children with congestive heart failure (CHF). STUDY DESIGN: Ninety-eight patients younger than 18 years hospitalized with dilated cardiomyopathy at a single institution between January 1, 2000, and December 31, 2009, were included. Retrospective review of their presenting complaints was recorded and analyzed according to 3 age groups: 0 to 1 year (infants), 1 to 10 years (children), and 11 to 18 years (adolescents) of age. RESULTS: Respiratory symptoms were common in all age groups (range, 56%-63%). Gastrointestinal complaints were also common in all age groups (42%, 28%, and 65%, respectively) and were more frequent than respiratory complaints in adolescents. Adolescents were likely to present with abdominal pain as their only complaint (10/43, 23%). Chest pain, syncope, or cardiac arrest occurred rarely. CONCLUSIONS: Abdominal complaints are a common component of the presenting symptom complex of CHF in pediatric dilated cardiomyopathy in all age groups. In adolescents, abdominal complaints occur more frequently than respiratory complaints and often in the absence of any other symptoms. Unlike CHF in adults, chest pain, arrhythmia, or cardiac arrest occurs rarely at presentation in pediatric patients. Recognition of the different presenting symptoms of heart failure in children by primary providers is crucial to ensuring prompt diagnosis and timely initiation of therapy.
The American journal of emergency medicine 02/2013; · 1.54 Impact Factor
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ABSTRACT: Background:
Risk factors for diastolic dysfunction in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigated the association of variants in hypoxia-response genes with phenotype severity in pediatric HCM.
Methods:
A total of 80 unrelated patients <21 y and 14 related members from eight families with HCM were genotyped for six variants associated with vascular endothelial growth factor A (VEGFA) downregulation, or hypoxia-inducible factor A (HIF1A) upregulation. Associations between risk genotypes and left-ventricular (LV) hypertrophy, LV dysfunction, and freedom from myectomy were assessed. Tissue expression was measured in myocardial samples from 17 patients with HCM and 20 patients without HCM.
Results:
Age at enrollment was 9 ± 5 y (follow-up, 3.1 ± 3.6 y). Risk allele frequency was 67% VEGFA and 92% HIF1A. Risk genotypes were associated with younger age at diagnosis (P < 0.001), septal hypertrophy (P < 0.01), prolonged E-wave deceleration time (EWDT) (P < 0.0001) and isovolumic relaxation time (IVRT) (P < 0.0001), and lower freedom from myectomy (P < 0.05). These associations were seen in sporadic and familial HCM independent of the disease-causing mutation. Risk genotypes were associated with higher myocardial HIF1A and transforming growth factor B1 (TGFB1) expression and increased endothelial-fibroblast transformation (P < 0.05).
Conclusion:
HIF1A-upregulation and/or VEGFA-downregulation genotypes were associated with more severe septal hypertrophy and diastolic dysfunction and may provide genetic markers to improve risk prediction in HCM.
Pediatric Research 11/2012; 72(6):583-92. · 2.70 Impact Factor
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ABSTRACT: A major limitation of pediatric heart transplantation is scarcity of pediatric donor organs, leading to longer waiting times and higher waiting list mortality. Current practice is to match potential pediatric recipients with donors by weight; however, we hypothesize height to be a better predictor of heart size as estimated by left ventricular end-diastolic diameter (LVEDd), as well as a novel measurement from the superior vena cava-right atrium junction to inferior vena cava-right atrium junction (SVC-IVC distance). Our ultimate objective is to present a more effective means of size-matching for pediatric heart transplantation.
Measurements of LVEDd and SVC-IVC distance were taken from 254 normal echocardiograms performed on individuals aged 7 days to 22 years, and correlated with demographic variables, including height, weight, and body surface area. Simulations were conducted using echocardiographic measurements and size parameters of past recipients with hypothetic donors to demonstrate practicality.
There was a linear relationship between height and SVC-IVC distance (R(2) = 0.904) and LVEDd (R(2) = 0.889), whereas the relationships with weight were logarithmic (SVC-IVC distance, R(2) = 0.855; LVEDd, R(2) = 0.880), and the relationships with body surface area were polynomial (SVC-IVC distance, R(2) = 0.880; LVEDd, R(2) = 0.884). Three simulations demonstrate improvements in efficiency of the size-matching process.
The use of height and a novel SVC-IVC distance measurement to evaluate heart size in potential pediatric heart transplant recipients and donors may allow for broadening of the donor pool and creation of a more efficient and accurate size-matching process. The prospective evaluation of these novel methods with respect to clinical outcomes is necessary.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 05/2012; 31(8):896-902. · 3.54 Impact Factor
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ABSTRACT: Previous studies have shown poor outcomes in pediatric heart transplant recipients with a high PRA or a positive direct donor-recipient cross-match. This study describes outcomes in patients with a positive cross-match at a large pediatric program. Pediatric heart transplant patients at a large single center between January 1993 and July 2009 were reviewed; those with cross-match data were analyzed. Cross-match data were available in 242/262 (92.4%) patients. Indications for transplant were cardiomyopathy (58%), CHD (32%), and retransplant (7%). PRA was ≥10% in 31/213 (14.6%) patients. A retrospective cross-match was positive in 17/31 (55%) patients with PRA ≥10% and 0/182 with PRA <10%. In positive cross-match patients, rejection frequency in the first year post-transplant was higher than negative cross-match patients (1.69 vs. 0.96 episodes/pt year, p = 0.014). There was no difference in rejection frequency after the first year post-transplant (0.18 vs. 0.12 episodes/pt year, p = 0.14). Overall survival was not significantly different between the groups with a median follow-up time of 4.5 yr. Heart transplantation in patients with a positive cross-match may result in good medium-term survival but a higher frequency of early rejection. Further investigation is warranted to define which patients with a positive cross-match will do poorly.
Pediatric Transplantation 02/2012; 16(1):29-35. · 1.48 Impact Factor
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ABSTRACT: Currently, pulmonary vascular resistance index (PVRI) >6 WU × m(2) (indexed units) is generally considered a contraindication to isolated orthotopic heart transplantation (OHT). However, this has been questioned in the literature.
A retrospective review was performed on all patients <18 years old who underwent primary OHT for cardiomyopathy. Data were collected with regard to demographics, pre-operative hemodynamics, need for pre-operative mechanical circulatory support, vasodilator reactivity and 30-day mortality (30dM). A receiver operating characteristic (ROC) curve was used to establish an optimal threshold. Uni- and multivariate logistic regressions were performed to assess the influence of PVRI on 30dM.
Complete data were available for 158 cardiomyopathy patients <18 years of age, who underwent primary OHT between June 1984 and November 2010. The ROC curve yielded a threshold of 9.290 indexed units. Four of 19 patients (21.1%) with PVRI >9 died in the first 30 days. In patients with PVRI <9, there was only 1 death among 139 patients (0.7%). Odds of mortality increased incrementally with PVRI as a continuous variable, with an odds ratio (OR) of 1.35 per indexed unit (95% confidence interval 1.12 to 1.63). PVRI was dichomotomized (PVRId) using the previously established threshold and revealed an increasing risk of mortality, OR 36.80 (95% confidence interval 3.86 to 350.90), with a PVRI of >9 indexed units.
Using a PVRI >6 as a contraindication to isolated OHT may be too restrictive. Patients with PVRI ≤9 do not appear to be at increased risk of early mortality. In patients with PVRI >9, 30-day survival was 78.9% in this study. This represents a viable alternative to heart-lung transplantation.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2012; 31(1):61-6. · 3.54 Impact Factor
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ABSTRACT: We reviewed the use of pediatric mechanical circulatory support before and after transplantation to examinine current results and future strategies.
All patients listed for transplantation from January 2000 to December 2010 who required either extracorporeal membrane oxygenation (ECMO) or ventricular assist device (VAD) support before ("intention to transplant") or after transplantation were included. Indications for mechanical assistance, age, weight, duration of support, complications while on support, causes of death, and overall actuarial survival were recorded.
Thirty-seven patients were received VADs; 32 (86.5%) survived to transplantation. Postoperative hemorrhagic or thrombotic complications affected all of those under 15 kg. One patient in the survivor cohort demonstrated focal neurologic findings. Three (8.1%) had panel reactive antibody levels of 10% or more while on device support; all received transplants. ECMO as an intention to bridge to transplantation was used in 28 patients; 7 died, 7 were weaned, and 14 were bridged to transplantation. Nineteen patients required ECMO after transplantation; 3 additional patients had percutaneous VAD support for late rejection. There was a significant (P = .02) difference in survival after listing for transplantation among those supported with ECMO, with VAD, and those not supported with a device. No difference in posttransplant survival was demonstrated between those patients supported with either ECMO or VAD before transplant compared with all others not bridged to transplantation.
Both VAD and ECMO support are highly effective means of bridging patients to transplantation and supporting patients after transplanatation. Ideally, the availability of smaller devices for children will have a favorable impact on the morbidity related to anticoagulation in the smallest patients.
The Journal of thoracic and cardiovascular surgery 12/2011; 143(2):344-51. · 3.41 Impact Factor
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ABSTRACT: Identification of heart transplant recipients at highest risk for a poor outcome could lead to improved posttransplantation survival. A chart review of primary heart transplantations from 1993 to 2006 was performed. Analysis was performed to evaluate the risk of graft loss for those with a transplantation age less than 1 year, congenital heart disease (CHD), elevated pulmonary vascular resistance (index > 6), positive panel reactive antibody or crossmatch, liver or renal dysfunction, mechanical ventilation, or mechanical circulatory support (MCS). Primary transplantation was performed for 189 patients. Among these patients, 37% had CHD, 23% had mechanical ventilation, and 6% had renal dysfunction. Overall graft survival was 82% at 1 year and 68% at 5 years. The univariate risk factors for graft loss included mechanical ventilation (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.15-3.18), CHD (HR, 1.68; 95% CI, 1.04-2.70), and renal dysfunction (HR, 3.05; 95% CI, 1.34-6.70). The multivariate predictors of graft loss were CHD (HR, 1.8; 95% CI, 1.02-2.64), mechanical ventilation (HR, 1.9; 95% CI, 1.13-3.10), and the presence of two or more statistically significant univariate risk factors (SRF) (HR, 3.8; 95% CI, 2.00-7.32). Mechanical ventilation, CHD, and the presence of two or more SRFs identify pediatric patients at higher risk for graft loss and should be considered in the management of children with end-stage heart failure.
Pediatric Cardiology 09/2011; 33(1):49-54. · 1.30 Impact Factor
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ABSTRACT: We report our initial experience with our newly developed percutaneous right-ventricular assist device (VAD) with CentriMag (perc CM-RVAD).
A flexible outflow cannula placed from the right internal jugular vein to the pulmonary artery and an inflow cannula placed from the femoral vein to the right atrium constituted the perc CM-RVAD. When needed, biventricular support was provided with left VAD (LVAD), either with a percutaneous LVAD placed through axillary or femoral artery access or with a fully implantable LVAD.
Between January 2009 and June 2010, all of the attempted patients successfully received perc CM-RVAD (n = 8). Mean blood pressure, heart rate, and central venous pressure showed a trend toward improvement after the perc CM-RVAD, with less inotrope/vasopressor requirement. Mixed venous oxygen saturation (SvO(2)) increased significantly from 64 ± 20 Torr to 78 ± 6 Torr (P < 0.01). The percutaneous VADs were explanted after myocardial recovery in seven patients; however, in three of these, perc CM-RVAD was used as a temporary bridge to other devices. One patient was bridged to a surgical biventricular assist device (BiVAD) and transferred back to the referring hospital on support. One death occurred due to multiple-organ failure 8 days after explantation of the RVAD with recovery.
Perc CM-RVAD was feasible and provided hemodynamic improvement.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 07/2011; 41(2):423-6. · 2.40 Impact Factor
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ABSTRACT: We have analyzed the impact of anti-HLA antibodies present in the patients' circulation prior and/or following heart transplantation in a population of 108 pediatric recipients. Anti-HLA class I and class II antibodies were monitored by traditional CDC using donor and panel T and B lymphocytes and by SPA for detection of DSA. There was a highly significant correlation between the development of AMR and presence of CDC- or SPA-detected DSA. However, the fraction of the transplant population which remained AMR-free was much higher among patients with SPA-detected compared to CDC-detected DSA. Furthermore, long-term graft survival was negatively affected only by cytotoxic, complement-fixing anti-HLA class I antibodies developing following transplantation. Anti-HLA class I or class II antibodies detected by SPA had no effect on long-term survival rates.
Pediatric Transplantation 03/2011; 15(5):458-64. · 1.48 Impact Factor
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ABSTRACT: Pulmonary hypertension causes increased morbidity and mortality in adults after heart transplantation. The effect of markedly elevated pulmonary vascular resistance (PVR) on post-transplant outcomes in children has not been well described.
Outcomes were compared in a retrospective study between 58 children with an elevated PVR index (PVRI) ≥ 6 U/m(2) and 205 children with a PVRI < 6 U/m(2). Patients who did and did not respond to acute vasodilator testing and patients who underwent transplant before (pre-1995) and after (post-1995) the availability of inhaled nitric oxide (iNO) were compared.
The pre-transplant diagnoses, and cardiopulmonary bypass and donor ischemic times were similar between the high and low PVRI groups. High PVRI patients were older at transplant (12 ± 6.2 vs 8 ± 7.1 years, p = 0.002). The post-transplant inotrope score was higher in the high PVRI group (12 ± 12 vs 2 ± 2, p = 0.0001) and 1-year survival was worse (76% vs 81%, p = 0.03). The PVRI fell to < 6 U/m(2) with acute vasodilator testing in 21 of 49 (42%) high PVRI patients. RV failure occurred in 4 (19%) of the responders and in 14 (50%) of the non-responders (p = 0.037). One responder (5%) and 4 non-responders (14%) died of RV failure. In the period after 1995, the year iNO became clinically available, the select group of high PVRI patients who received iNO preemptively had a lower incidence of post-transplant RV failure than the group that did not receive preemptive iNO (13% vs 54%, p = 0.04).
Pre-transplant vasodilator testing identified patients at higher risk for RV failure. Patients who did not respond to vasodilator testing had an increased incidence of RV failure and death from RV failure. Preemptive use of iNO was associated with a decreased incidence of RV failure.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2011; 30(6):659-66. · 3.54 Impact Factor
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ABSTRACT: The prognostic role of CD20 expression and Epstein-Barr virus (EBV) positivity in post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT) in paediatric patients is poorly understood. We retrospectively examined the relationship of CD20 and EBV with the time interval from SOT to PTLD diagnosis, and PTLD-related event-free (EFS) and overall survival (OS) in 45 consecutive PTLD patients (≤25 years) following SOT. These 45 paediatric SOT patients (28 heart, 11 liver, six kidney) were diagnosed with PTLD 45 months (mean; SD 43; range 4-153; median 24·5) after SOT, with PTLD diagnosis at 118 months (mean) (SD 77; range 14-287) of age. Of 40 evaluable tumours (11 monomorphic, 19 polymorphic, five early lesions, five rare subtypes), 32 (80%) had detectable EBV and 28 (70%) were classified as CD20(+) . Patients whose PTLD expressed CD20 or EBV had shorter intervals between SOT and PTLD onset (28 vs. 64 or 77 months for CD20 and EBV respectively) (P < 0·02), even after adjusting for age at SOT. Patients with CD20(+) tumours had higher 5-year PTLD-related EFS (83·7% vs. 28·6%, P < 0·001) and OS (95·8% vs. 56·3%, P = 0·01). EBV expression was unrelated to PTLD-related EFS or OS. CD20 expression is associated with timing of development of PTLD and predicts survival in PTLD diagnosed following paediatric SOT.
British Journal of Haematology 01/2011; 152(6):733-42. · 4.94 Impact Factor
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ABSTRACT: Post-transplant lymphoproliferative disorder (PTLD) contributes to morbidity and mortality after transplantation. We examined the effect of immunosuppressive regimen on the risk of developing PTLD after pediatric heart transplantation.
The 324 pediatric heart transplant patients at 2 children's hospitals were retrospectively reviewed for the primary outcome of PTLD development. Patient demographics, rejection frequency, serum cyclosporine and tacrolimus levels, induction therapy, donor and recipient Epstein-Barr virus, and cytomegalovirus serologic status were reviewed and comparisons made between immunosuppressive regimens. Comparisons were also made between transplantation in the early (1984-1995) and late (1996-2008) eras to help account for changes in clinical protocols that occurred during the study period.
PTLD developed in 33 (10%), of whom 109 (34%) were treated with tacrolimus. PTLD developed in 15% of those treated with tacrolimus compared with 8% of patients treated solely with cyclosporine. Tacrolimus use was a significant predictor of PTLD, with a hazard ratio [HR] of 4.04 (95% confidence interval [CI], 2.03-8.02; p = 0.0001). Neither Epstein-Barr virus, cytomegalovirus donor/recipient status, nor gender predicted PTLD development. Younger age at transplant, higher rejection frequency, and induction therapy predicted PTLD development by univariate analysis. Multivariate modeling demonstrated that tacrolimus use (HR, 7.03; 95% CI, 2.87-17.2; p < 0.001) remained an independent predictor of PTLD, when controlling for age, era of transplantation, induction therapy, and rejection frequency.
This study suggests the use of tacrolimus after pediatric heart transplantation is independently associated with an increased risk of PTLD compared with cyclosporine alone.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2010; 30(4):420-5. · 3.54 Impact Factor
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ABSTRACT: Left-ventricular noncompaction (LVNC) is an echocardiographic finding of increasing frequency in pediatrics; however, predictors of outcomes have been difficult to identify. We conducted a retrospective review of pediatric patients at the Morgan Stanley Children's Hospital of New York from January of 1993 to September of 2009 to identify predictors of the primary outcome of death or heart transplantation. LVNC was identified in 50 patients, 34 of them < 1 year of age. Death or transplantation occurred in 26 patients, with a median survival of 1.17 years after presentation. Patients surviving 1 year after presentation had 75% conditional survival, and patients surviving 2 years after presentation had 92% conditional survival. Hemodynamic instability, poor ventricular function, and LV dilatation were each independent predictors of poor outcome. Of the 21 patients who presented with hemodynamic instability, 17 died or underwent transplantation at a median of 0.08 years after presentation. In conclusion, LVNC is recognized more in younger patients; however, age is not a predictor of outcome. Patients who present with hemodynamic instability and poor ventricular function have decreased transplant-free survival, and most poor outcomes occur within the first year after presentation. Therefore, early listing for transplant may lead to better outcomes in this population.
Pediatric Cardiology 12/2010; 32(4):406-12. · 1.30 Impact Factor
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Khurram Shahzad,
Quratul Ain Aziz,
Jean-Paul Leva,
Martin Cadeiras,
Eric K Ho,
George Vlad,
E Rodica Vasilescu,
Farhana Latif,
Anshu Sinha,
Elizabeth Burke, Linda J Addonizio,
Susan W Restaino,
Charles C Marboe,
Nicole Suciu-Foca,
Yoshifumi Naka,
Donna Mancini,
Mario C Deng
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ABSTRACT: Graft dysfunction (GD) after heart transplantation (HTx) is a major cause of morbidity and mortality. The impact of different pathophysiologic mechanisms on outcome is unknown. In this large, single-center study we aimed to assess the incidence of GD and compare the outcomes with different histopathologic mechanisms of rejection.
We analyzed a data set of 1,099 consecutive patients after their HTx at Columbia University Medical Center between January 1994 and March 2008, and identified all patients hospitalized with new-onset GD. Based on the histopathologic data, patients were divided into GD-unexplained (Group-GD-U), GD-antibody-mediated rejection (Group-GD-AMR), GD-cardiac allograft vasculopathy (Group-GD-CAV) and GD-acute cellular rejection (Group-GD-ACR) groups. We compared the in-hospital and 3-, 6- and 12-month mortality across these groups using the chi-square test. We also compared the 3-, 6- and 12-month survival curves across groups using the log-rank test.
Of 126 patients (12%) identified with GD, complete histology data were available for 100 patients. There were 21, 20, 27 and 32 patients identified in Group-GD-U, Group-GD-AMR, Group-GD-CAV and Group-GD-ACR, respectively. The in-hospital mortality rates were 52%, 20%, 15% and 6%, respectively. The in-hospital mortality rate was significantly higher in Group-GD-U compared with all other groups (p = 0.0006). The 3-, 6- and 12-month survival rate was also significantly lower in Group-GD-U compared with all other groups.
A significant proportion of patients presenting with new-onset GD have unexplained histopathology. Unexplained GD is associated with a significantly higher mortality rate. New diagnostic tools are necessary to better understand and detect/predict this malignant phenotype.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 10/2010; 30(2):194-203. · 3.54 Impact Factor
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ABSTRACT: The ability of serum B-type natriuretic peptide levels (BNP) to predict outcomes in children with heart failure (HF) has not been well demonstrated. This study was designed to determine whether BNP levels predict outcomes in patients with moderate symptomatic HF.
We investigated whether enrollment BNP levels for the Pediatric Carvedilol Trial were associated with baseline characteristics. Freedom from a composite end point of HF hospitalization, death, or transplantation at 9 months was compared using a threshold BNP level identified using receiver operating curve analysis. Median BNP level was 110 pg/mL (interquartile range, 22.4 to 342.0 pg/mL) in 138 subjects. Median age was 3.4 years (interquartile range, 1.1 to 11.0 years). Diagnoses were cardiomyopathy (60%) and congenital heart disease (40%); 73% had a systemic left ventricle. BNP levels correlated moderately with left ventricular ejection fraction (R=0.39, P<0.001) but did not differ by HF class, age, diagnosis, sex, ventricular morphology, or left ventricular end-diastolic dimension Z-score (R=0.19). Outcome events included 25 HF hospitalizations, 4 deaths, and 2 transplants. Sensitivity was 71% and specificity 63%, for a BNP cutoff value of 140 pg/mL. BNP ≥140 pg/mL (hazard ratio, 3.7; 95% confidence interval, 1.62 to 8.4; P=0.002) and age >2 years (hazard ratio, 4.45; 95% confidence interval, 1.68 to 12.04; P=0.003) were independently associated with worse outcomes.
In children with moderately symptomatic HF, BNP ≥140 pg/mL and age >2 years identified subjects at higher risk for worse outcome. Further validation is needed to determine the BNP levels necessary to stratify risk in other pediatric cohorts.
Circulation Heart Failure 09/2010; 3(5):606-11. · 6.29 Impact Factor
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Martin Cadeiras,
Khurram Shahzad,
Manju M John,
Dorota Gruber,
Manuel von Bayern,
Scott Auerbach,
Anshu Sinha,
Farhana Latif,
Sreevalsa Unniachan,
Sarfaraz Memon,
Seema Mital,
Susan Restaino,
Charles C Marboe, Linda J Addonizio,
Mario C Deng
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ABSTRACT: As acute cellular cardiac allograft rejection is a systemic process affecting the entire organism, we hypothesized that scores of a peripheral blood mononuclear cell gene expression profiling (GEP) test developed and validated to rule out International Society of Heart and Lung Transplantation (ISHLT) grade > or = 3A/2R acute cellular cardiac allograft rejection also reflects biologically plausible changes of the routinely assessed clinical parameters.
We retrospectively analyzed 76 patients who underwent GEP testing, at the time of their routine clinical follow-up in our Institution between February 1, 2006 and January 31, 2007. Data were analyzed with t-test, nonparametric tests, bivariate Spearman's correlation, and multivariate linear regression modeling.
More activated GEP-score correlated with longer corrected QT (QTc)-interval (r = 0.377, p = 0.001, n = 63), longer QRS duration (r = 0.231, p = 0.03, n = 66), higher heart rate (r = 0.221, p = 0.037, n = 66), higher serum creatinine (r = 0.26, p = 0.01, n = 75), higher gamma-glutamyl transferase (GGT) GGT (r = 0.266, p = 0.037, n = 46), lower pulmonary artery oxygen saturation (r = -0.313, p = 0.003, n = 76), lower platelet count (r = -0.372, p = 0.001, n = 74), lower monocyte count (r = -0.208, p = 0.040, n = 72), and lower high-density lipoprotein (HDL) HDL level (r = -0.242, p = 0.041, n = 53). Multivariate analysis showed a significant amount of variance in the GEP score independently explained by the variability of QTc-interval (beta = 1.998, p = 0.001) and platelet count (beta = -1.540, p = 0.017). Post hoc analysis of the 11 individual GEP-classifier genes showed WDRA40 (p = 0.02) and ras homolog gene family, member U (RHOU) RHOU (p = 0.01) independently related to mixed venous O(2)Sat%.
A GEP test developed and validated to detect the absence of cardiac rejection correlates with electrocardiographic and hemodynamic cardiac parameters as well as renal, hepatic, bone marrow, and lipid metabolism parameters suggesting a complex relationship between rejection, leukocytes, and organ function within the continuum between alloimmunological quiescence and rejection.
Clinical Transplantation 09/2009; 24(3):321-7. · 1.67 Impact Factor
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Scott R Auerbach,
Cedric Manlhiot,
Sushma Reddy,
Caroline Kinnear,
Marc E Richmond,
Dorota Gruber,
Brian W McCrindle,
Liyong Deng,
Jonathan M Chen, Linda J Addonizio,
Wendy K Chung,
Seema Mital
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ABSTRACT: This study sought to investigate the influence of recipient renin-angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation.
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.
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)-beta, and tumor necrosis factor (TNF)-alpha during rejection and quiescence.
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-beta were markedly upregulated during rejection in patients with >/=2 high-risk RAAS genotypes.
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.
Journal of the American College of Cardiology 06/2009; 53(20):1909-17. · 14.16 Impact Factor
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ABSTRACT: The aim of this study was to evaluate diastolic function in pediatric cardiac transplant recipients free of acute rejection using tissue Doppler. E' and A' velocities at the mitral, septal, and tricuspid annuli in 31 pediatric heart transplant recipients free of acute rejection were compared with 28 controls and with previously published pediatric normative data. E' velocities were lower in the transplant group at the mitral (0.13 +/- 0.04 vs. 0.2 +/- 0.04 m/s, p < 0.0001), septal (0.1 +/- 0.03 vs. 0.14 +/- 0.03 m/s, p = 0.001), and tricuspid annuli (0.1 +/- 0.04 vs. 0.17 +/- 0.04 m/s, p < 0.0001). A' velocities were also lower in the transplant group at the septal (0.04 +/- 0.01 vs. 0.06 +/- 0.01 m/s, p = 0.001) and tricuspid annuli (0.06 +/- 0.02 vs. 0.1 +/- 0.03 m/s, p < 0.00001). E' and A' were abnormally low at the mitral annulus in 31% and 13%, septal annulus in 50% and 21%, and tricuspid annulus in 63% and 36% of the subjects, respectively. Abnormalities in tissue Doppler-derived diastolic myocardial velocities are common in pediatric cardiac transplant recipients free of acute rejection.
Pediatric Cardiology 07/2008; 29(4):749-54. · 1.30 Impact Factor
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ABSTRACT: Cardiac retransplantation is often the only therapy to treat GV or other causes of allograft failure. Previous reports of retransplantation have conflicting results. In this series of 18 re-transplants in 16 patients from 1984-2005, indications for retransplantation were: GV (67%); GV with cellular rejection (28%); acute graft failure (2.5%); and chronic graft failure (2.5%). Mean age at retransplantation was 12.3 (range: 0.7-22) years with a mean primary graft survival of 5.3 years (range: 8 days-10.5 years). There was no short-term mortality with only three deaths at 4, 10, and 16 years post-retransplantation. Fourteen of 18 patients had risk factors for adverse outcomes following retransplantation: ECMO support in one patient prior to retransplantation; impaired renal function in three patients; elevated panel reactive antibody screen in seven patients; a history of PTLD in five patients; and a recent episode of rejection (13-36 days) in four patients. One-, five- and ten-year survival after retransplantation was 100%, 83% and 66%, respectively, comparable to survival after primary transplantation. Freedom from rejection was not significantly different between primary and retransplantations. All patients who underwent treatment for PTLD had excellent results after retransplantation with one recurrence 16 months after retransplant. Overall, patients had excellent survival after retransplantation even in those with risk factors for poor outcome.
Pediatric Transplantation 10/2007; 11(6):615-23. · 1.48 Impact Factor
