Marc E. Richmond

BNP Levels Predict Outcome in Pediatric Heart Failure Patients: Post-hoc Analysis of the Pediatric Carvedilol Trial

Background— 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. Methods and Results— 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 2 years (hazard ratio, 4.45; 95% confidence interval, 1.68 to 12.04; P =0.003) were independently associated with worse outcomes. Conclusions— 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.Background—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. Methods and Results—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. Conclusions—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.

In Utero Cardiac Gene Transfer via Intraplacental Delivery of Recombinant Adenovirus

BACKGROUND The relationship among the maternal, placental, and uniquely shunted embryonic circulation was explored to provide access to the embryonic cardiovascular system in utero. Manipulation of gene expression in the developing heart would be particularly useful for studying the effects of altered gene expression on cardiac development and in the etiology of congenital cardiac anomalies. METHODS AND RESULTS Dye studies demonstrated that intraplacental injection allows direct access to the embryonic cardiac and systemic circulation. To evaluate the efficacy of cardiac gene transfer using this approach, replication-deficient recombinant adenoviral vectors encoding luciferase or beta-galactosidase as reporter genes were injected intraplacentally into embryonic day (E)12.5 murine embryos, an age at which the mass of the heart was observed to be large compared with other organs. Embryos were assayed for transgene expression at E15.5 and at birth. Survival rates at these times were similar among vector-injected and control groups. At E15.5 and at birth, luciferase activity within the heart was 9- and 23-fold higher, respectively, than in the remainder of the embryo, although levels of expression were generally lower at birth than during embryonic life. Beta-galactosidase expression was observed within all regions of the embryonic heart and was localized to approximately 15% of atrial and ventricular cells. CONCLUSIONS Intraplacental delivery of adenovirus at embryonic day 12.5 results in somatic gene transfer to the murine embryonic heart, which persists at least until birth. The combination of intraplacental injection to directly access the fetal coronary circulation and injection at E12.5 when the mass of the heart is large compared with other organs results in transgene expression in cardiac cells. Intraplacental injections early in embryonic life may thus be useful to study the effects of temporal manipulation of gene expression on cardiac development and disease.

What is high risk? Redefining elevated pulmonary vascular resistance index in pediatric heart transplantation

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Outcomes of Cardiac Transplantation in Single-Ventricle Patients With Plastic Bronchitis: A Multicenter Study

To the Editor: Plastic bronchitis (PB) is a rare condition characterized by formation of airway casts that obstruct the bronchial tree and cause respiratory failure. In the congenital cardiac population, PB occurs mostly in patients with single ventricle (SV) defects undergoing Fontan palliation.

Optimized temporary biventricular pacing acutely improves intraoperative cardiac output after weaning from cardiopulmonary bypass: A substudy of a randomized clinical trial

OBJECTIVE Permanent biventricular pacing benefits patients with heart failure and interventricular conduction delay, but the importance of pacing with and without optimization in patients at risk of low cardiac output after cardiac surgery is unknown. We hypothesized that pacing parameters independently affect cardiac output. Accordingly, we analyzed aortic flow measured with an electromagnetic flowmeter in patients at risk of low cardiac output during an ongoing randomized clinical trial of biventricular pacing (n = 11) versus standard of care (n = 9). METHODS A substudy was conducted in all 20 patients in both groups with stable pacing after coronary artery bypass grafting, valve surgery, or both. Ejection fraction averaged 33% ± 15%, and QRS duration was 116 ± 19 ms. Effects were measured within 1 hour of the conclusion of cardiopulmonary bypass. Atrioventricular delay (7 settings) and interventricular delay (9 settings) were optimized in random sequence. RESULTS Optimization of atrioventricular delay (171 ± 8 ms) at an interventricular delay of 0 ms increased flow by 14% versus the worst setting (111 ± 11 ms, P < .001) and 7% versus nominal atrioventricular delay (120 ms, P < .001). Interventricular delay optimization increased flow 10% versus the worst setting (P < .001) and 5% versus nominal interventricular delay (0 ms, P < .001). Optimized pacing increased cardiac output 13% versus atrial pacing at matched heart rate (5.5 ± 0.5 vs 4.9 ± 0.6 L/min, P = .003) and 10% versus sinus rhythm (5.0 ± 0.6 L/min, P = .019). CONCLUSIONS Temporary biventricular pacing increases intraoperative cardiac output in patients with left ventricular dysfunction undergoing cardiac surgery. Atrioventricular and interventricular delay optimization maximizes this benefit.

Balloon atrial septostomy in pulmonary arterial hypertension: Effect on survival and associated outcomes

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive disease that, without early identification and treatment, may lead to right heart failure, multi-organ dysfunction and early death. In severe PAH, in addition to maximal medical therapy, balloon atrial septostomy (BAS) may be used for palliation and as a bridge to lung transplantation. We present our contemporary institutional experience utilizing BAS in adult and pediatric patients with severe PAH. METHODS We performed a retrospective analysis of 46 BASs performed in 32 patients with PAH from 2002 to 2013. Data obtained included vital status, functional class, medications, hemodynamic measurements from right heart catheterizations and biomarkers. Lung transplantation-free and repeat-BAS-free survival was analyzed. RESULTS Median age at BAS was 23 (range 1 to 56) years. The most common indications were symptomatic right heart failure (21 of 46 patients) and pre-syncope/syncope (19 of 46 patients); 69% of patients were WHO Functional Class III or IV pre-BAS. There were no procedural complications or deaths. There were no significant differences in biomarkers or hemodynamic findings between pre-BAS and 1 year or latest follow-up. Seven patients were successfully bridged to lung transplantation. Lung transplantation-free and repeat-BAS-free survival at 30 days, 1 year and 5 years was 87%, 61% and 32%, respectively. CONCLUSIONS In our experienced center, BAS was shown to be safe in patients with severe PAH on maximal medical management, with no procedural deaths or complications. BAS was safely used as a bridge to lung transplantation or to alleviate right heart failure symptoms and/or syncope. Other potential benefits for end-organ function and overall survival remain to be determined.

Surgical Interventions for Atrioventricular Septal Defect Subtypes: The Pediatric Heart Network Experience

BACKGROUND The influence of atrioventricular septal defect (AVSD) subtype on outcomes after repair is poorly understood. METHODS Demographic, procedural, and outcome data were obtained 1 and 6 months after AVSD repair in an observational study conducted at 7 North American centers. RESULTS The 215 AVSD patients were subtyped as 60 partial, 27 transitional, 120 complete, and 8 with canal-type VSD. Preoperatively, transitional patients had the highest prevalence of moderate or severe left atrioventricular valve regurgitation (LAVVR, p = 0.01). At repair, complete AVSD and canal-type VSD patients, both with the highest prevalence of trisomy 21 (p < 0.001), were younger (p < 0.001), had lower weight-for-age z scores (p = 0.005), and had more associated cardiac defects (p < 0.001). Annuloplasty was similar among subtypes (p = 0.91), with longer duration of ventilation and hospitalization for complete AVSD (p < 0.001). Independent predictors of moderate or severe LAVVR at the 6-month follow-up were older log(age) at repair (p = 0.02) but not annuloplasty, subtype, or center (p > 0.4). Weight-for-age z scores improved in all subtypes at the 6-month follow-up, and improvement was similar among subtypes (p = 0.17). CONCLUSIONS AVSD subtype was significantly associated with patient characteristics and clinical status before repair and influenced age at repair. Significant postoperative LAVVR is the most common sequela, with a similar prevalence across centers 6 months after the intervention. Annuloplasty failed to decrease the postoperative prevalence of moderate or severe LAVVR at 6 months. After accounting for age at repair, AVSD subtype was not associated with postoperative LAVVR severity or growth failure at 6 months. Further investigation is needed to determine if interventional strategies specific to AVSD subtype improve surgical outcomes.

The effect of cardiopulmonary bypass prime volume on the need for blood transfusion after pediatric cardiac surgery.

OBJECTIVE There is increasing awareness that erythrocyte transfusions after pediatric cardiac surgery have deleterious effects. Despite reports of decreased transfusion requirements associated with smaller cardiopulmonary bypass circuits, the relationship between circuit prime volume and need for transfusion has not been systematically examined. METHODS Pediatric patients at our institution who underwent cardiopulmonary bypass between January 2005 and December 2010 were reviewed. Demographics, intraoperative data, and transfusion of packed red blood cells were retrospectively recorded. Cardiopulmonary bypass prime volume was indexed by patient body surface area. Logistic regression analysis was used to correlate these variables with need for transfusion. RESULTS In the perioperative period, 1912 patients received transfusions and 266 did not. In univariate analysis, indexed prime volume was a significant predictor of transfusion (odds ratio, 1.007; P < .001). Other significant variables in univariate analysis included age, surgeon, Risk Adjustment for Congenital Heart Surgery 1 (RACHS-1) category, preoperative hemoglobin, total bypass time, aortic crossclamp time, use and duration of deep hypothermic circulatory arrest, lowest body core temperature, and cardiopulmonary bypass flow rate. Previous cardiac surgery was not a significant predictor. In multivariable analysis controlling for RACHS-1 category, surgeon, minimal core body temperature, and preoperative hemoglobin, indexed prime volume remained an independent predictor of transfusion (odds ratio, 1.006; 95% confidence interval, 1.005-1.007, P < .001). CONCLUSIONS Perioperative need for transfusion in pediatric cardiac surgical patients is independently related to the prime volume of the cardiopulmonary bypass circuit. It therefore seems prudent to minimize circuit prime volumes to avoid unnecessary use of blood products.

Role of immunosuppression regimen in post-transplant lymphoproliferative disorder in pediatric heart transplant patients

BACKGROUND 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. METHODS The 324 pediatric heart transplant patients at 2 childrens 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. RESULTS 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. CONCLUSIONS This study suggests the use of tacrolimus after pediatric heart transplantation is independently associated with an increased risk of PTLD compared with cyclosporine alone.

Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation

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)-beta, and tumor necrosis factor (TNF)-alpha 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-beta 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.