Safety and efficacy of nesiritide in pediatric heart failure.

BACKGROUND: We hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal function in pediatric patients. METHODS AND RESULTS: We analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 mcg.kg.min without a bolus and titrated to a maximum of 0.03 mcg.kg.min, in 0.005-mcg.kg.min increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly (P = .001). Urine output increased significantly on Days 1 and 3 (P < or = .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL (P < or = .001). In the substudy, aldosterone levels decreased from 37.5 +/- 57.1 to 20.5 +/- 41.9 ng/dL (P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension. CONCLUSIONS: Nesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.

Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children.

BACKGROUND: Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of LAMP2 mutations in an unselected pediatric HCM population. METHODS AND RESULTS: LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining. CONCLUSIONS: LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.

Outpatient continuous parenteral inotropic therapy as bridge to transplantation in children with advanced heart failure.

BACKGROUND: Advanced heart failure in children is associated with high morbidity and mortality and is often refractory to standard medical therapy. The purpose of this study was to review our institutional experience with the use of outpatient parenteral inotropic therapy (PIT) for advanced chronic heart failure in children. METHODS AND RESULTS: We reviewed the medical records of all patients treated with PIT as outpatients. Seven patients received outpatient PIT from 2/99 to 1/05 (mean age was 14.6 years +/- 3.7). Median duration of therapy was 10 weeks (range 4-84 weeks). The mean number of emergency department visits per patient was greater before starting PIT than after starting PIT (2.3 +/- 1.8 versus 1.1 +/- 2.2, P < .05). The mean number of hospital admissions from exacerbation of heart failure symptoms decreased after starting PIT (2.1 +/- 1.3 versus 0.6 +/- 0.8, P < .05). Mean EF% in patients with systolic dysfunction improved while on therapy (30 +/- 14% before versus 39 +/- 16% after, P < .05). There was 1 death and 5 complications in 2 patients. Six patients were successfully bridged to transplantation. CONCLUSION: Outpatient continuous parenteral inotropic therapy may serve as a successful bridge to cardiac transplantation in selected pediatric outpatients.

Short-term mechanical unloading and reverse remodeling of failing hearts in children.

BACKGROUND: Mechanical support using a left ventricular assist device (LVAD) can lead to functional recovery of the myocardium in patients with end-stage heart failure (HF). Molecular remodeling, cytoskeletal disruption, and apoptosis activation are associated with abnormal gene expression in the failing ventricular myocardium of HF subjects and can normalize in response to medium- and long-term mechanical unloading in adults. However, there is little knowledge of the changes in gene expression after short-term mechanical support in children with HF. METHODS: We evaluated left ventricular biopsies from 4 children with HF. The children had implantation of a continuous- or a pulsatile-flow LVAD for 8 to 16 days before undergoing heart transplantation. At the time of LVAD insertion and removal, we performed quantitative real-time polymerase chain reaction (QPCR) to study the expression of 326 genes encoding for structural, transcriptional, and signaling pathways proteins, and immunoblot analysis on dystrophin and apoptotic factors. RESULTS: Short-term LVAD therapy significantly decreased brain natriuretic peptide (BNP) levels from pre-LVAD (3,584.5 +/- 378.3 pg/ml [95% CI]) to post-LVAD (447.5 +/- 52.7 pg/ml [95% CI]) in 2 patients in whom comparative BNP measurements were available. In addition, short-term LVAD therapy reduced HF and apoptosis markers, whereas it upregulated structural proteins, including dystrophin, as well as pro-hypertrophic and pro-inotropic markers. Furthermore, LVAD therapy normalized expression of genes involved in calcium homeostasis, cell growth, and differentiation. CONCLUSIONS: Our pilot study suggests that even short-term LVAD therapy in children with severe HF can reverse molecular remodeling. This favorable effect should be taken into consideration in eligible children with significant ventricular dysfunction.

Viral epidemiologic shift in inflammatory heart disease: the increasing involvement of parvovirus B19 in the myocardium of pediatric cardiac transplant patients.

BACKGROUND: Detection of viral genome in rejecting cardiac transplant patients has been reported, with coxsackievirus and adenovirus causing premature graft failure. Recently, parvovirus B19 (PVB19) genome in myocardial samples has been increasingly reported, but its role in cardiac pathology and effect on transplant graft survival are unknown. The objectives of this study were to determine if changes in the viruses identified in the myocardium represent an epidemiologic shift in viral myocardial disease and whether PVB19 adversely affects transplant graft survival. METHODS: From September 2002 to December 2005, nested polymerase chain reaction was used to evaluate endomyocardial biopsy specimens for 99 children (aged 3 weeks-18 years) with heart transplants for the presence of viral genome. Cellular rejection was assessed by histology of specimens. Transplant coronary artery disease (TCAD) was diagnosed by coronary angiography or histopathology. RESULTS: Specimens from 700 biopsies were evaluated from 99 patients; 121 specimens had viral genome, with 100 (82.6%) positive for PVB19, 24 for Epstein-Barr virus (EBV; 7 positive for PVB19 and EBV), 3 for CMV, and 1 for adenovirus. Presence of PVB19 genome did not correlate with rejection score, nor did a higher viral copy number. Early development of advanced TCAD (p < 0.001) occurred in 20 children with persistent PVB19 infection (> 6 months). CONCLUSIONS: PVB19 is currently the predominant virus detected in heart transplant surveillance biopsy specimens, possibly representing an epidemiologic shift. Cellular rejection does not correlate with the presence or quantity of PVB19 genome in the myocardium, but children with chronic PVB19 infection have increased risk for earlier TCAD, supporting the hypothesis that PVB19 negatively affects graft survival.

Viral endomyocardial infection is an independent predictor and potentially treatable risk factor for graft loss and coronary vasculopathy in pediatric cardiac transplant recipients.

OBJECTIVES: This study sought to evaluate the outcome and prevalence of viral endomyocardial infection after cardiac transplantation. BACKGROUND: Viral myocardial infection causes heart failure, but its role after cardiac transplantation is unclear. We hypothesized that viral infection of the cardiac allograft reduces graft survival. METHODS: Between June 1999 and November 2004, 94 pediatric cardiac transplant patients were screened for the presence of viral genome in serial endomyocardial biopsies (EMBs) using polymerase chain reaction (PCR) assays. Graft loss, advanced transplant coronary artery disease (TCAD), and acute rejection (AR) were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan-Meier and Cox regression analyses. From November 2002 to November 2004, intravenous immunoglobulin therapy (IVIG) was administered to patients with PCR-positive EMBs. The outcomes of the IVIG-treated, PCR-positive patients (n = 20) were compared with IVIG-untreated, PCR-positive patients (n = 17). RESULTS: Viral genomes were detected in EMBs from 37 (39%) patients; parvovirus B19, adenovirus, and Epstein-Barr virus (EBV) were the most common. The PCR-positive group (n = 37, 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57, 25% graft loss at 8.7 years) and developed advanced TCAD prematurely (p = 0.001). The number of AR episodes was similar in both groups. On multivariate analysis, presence of viral genome was an independent risk factor for graft loss (relative risk: 4.2, p = 0.015). The time to advanced TCAD after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend toward improved graft survival (p = 0.06). CONCLUSIONS: Viral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients. This effect appears to be mediated through premature development of advanced TCAD. IVIG therapy in this subgroup may improve survival and merits further investigation.

Assessment of the Cylex ImmuKnow cell function assay in pediatric heart transplant patients.

BACKGROUND: The Cylex ImmuKnow (Cylex, Columbia, MD) cell function assay (CICFA) is a commercially available test of immune response that purportedly identifies solid organ transplant patients at risk for either acute rejection (AR) or infection. Data on the utility of this test in pediatric heart transplant patients are very limited. This study tested the hypothesis that CICFA is a clinically useful test in this transplant population. METHODS: All children undergoing heart transplantation at the study center (1989-2006) for whom CICFA levels were obtained were reviewed. The association of CICFA levels with episodes of AR and significant infections was determined. RESULTS: Among 83 patients (34 girls, 41%), 367 CICFA levels were obtained (median, 4.0; interquartile range [IQR], 2.0-6.0 per patient). There were 26 episodes of AR in 17 patients (20%) and 38 infections in 34 patients (41%). CICFA levels were similar among patients with AR at the time of the CICFA measurement (median, 325 [IQR, 163-480] adenosine triphosphate [ATP] ng/ml) vs patients without AR (median, 330 [IQR, 227-441] ATP ng/ml; p = 0.36). CICFA levels were similar among patients with infections within 1 month of CICFA measurement (median, 295 [IQR, 216-366] ATP ng/ml) and those without infections (median, 330 [IQR, 226-453] ATP ng/ml; p = 0.24). CONCLUSIONS: The CICFA is not predictive of AR or significant infections in pediatric heart transplant patients. On the basis of the available evidence, this assay cannot be recommended as part of the routine management of pediatric heart transplant patients.

Frequency of cardiac death in children with idiopathic dilated cardiomyopathy.

The prognosis in children with idiopathic dilated cardiomyopathy (IDC) is guarded, with the 5-year mortality rate ranging from 14% to 50%, owing to sudden cardiac death (SCD) or pump failure. The risk factors for SCD in adults with IDC include asymptomatic nonsustained ventricular tachycardia and poor left ventricular function. It is unclear whether these findings can be extrapolated to the pediatric population. A retrospective review of all patients with the diagnosis of IDC seen at a single institution from 1990 to 2004 was performed. A total of 85 patients (46 males), with a median age of 3.8 years (0 days to 17.3 years) were studied. The mean left ventricular ejection fraction was 25 +/- 12% (median 23%, range 45% to 45%) at presentation. The following arrhythmias occurred at presentation or during the initial hospitalization: nonsustained ventricular tachycardia in 6, sustained ventricular tachycardia or fibrillation in 1, supraventricular arrhythmias in 6, and both atrial and ventricular arrhythmias in 1. During a subsequent hospitalization or outpatient follow-up, 7 patients had the following arrhythmias: supraventricular arrhythmias in 2, nonsustained ventricular tachycardia in 4, and both atrial and ventricular arrhythmias in 1. The cumulative survival rate was 40% at a mean follow-up of 6.2 years (95% confidence interval 4.4 to 8.1). One single episode of SCD occurred in 1 patient without a history of sustained arrhythmias. In conclusion, in children with IDC, despite the low left ventricular ejection fraction and presence of ventricular arrhythmias, only one episode of SCD occurred in this group of patients. Given the 1% incidence of SCD in this cohort, the use of implantable cardioverter-defibrillators as primary prevention in children with IDC might not be indicated.

Risk factors and mode of death in isolated hypertrophic cardiomyopathy in children.

OBJECTIVES: This study was designed to review outcomes of pediatric isolated hypertrophic cardiomyopathy (HCM) managed uniformly at a single institution and assess whether reported adult risk factors for sudden death are predictive in pediatric HCM. BACKGROUND: Cardiac death in HCM occurs suddenly (SCD) or may be nonsudden (non-SCD). Little data exists on non-SCD in children. Risk factors for SCD in adult HCM are characterized and consensus management strategies detailed. Their application to children is uncertain and treatment strategies vary. METHODS: A retrospective cohort study of children with HCM was performed. Primary end points were cardiac death and transplantation. Frequency and outcomes of known adult risk factors were assessed. Outcomes analysis was performed using Kaplan-Meier curves and Cox regression analysis. RESULTS: Ninety-six patients were included. The average age at diagnosis was 10.6 +/- 5.4 years, and mean follow-up was 6.4 +/- 5.2 years. Primary end points occurred in 11 patients over the 20-year follow-up (11%), 4 underwent cardiac transplant and 7 died (3 suddenly). Extreme left ventricular hypertrophy (z-score: >6) and an abnormal blood pressure response to exercise were predictive of non-SCD (p < 0.02 and p < 0.03, respectively). Kaplan-Meier survival analysis predicts an 82% survival over a 20-year period. CONCLUSIONS: In children with isolated HCM managed primarily with exercise restriction and medication, cardiac death occurred infrequently. Non-SCD or transplant was at least as common as SCD. Extreme left ventricular hypertrophy and blunted blood pressure response to exercise were associated with an increased risk of non-SCD.

Myocardial pro-inflammatory cytokine expression and cellular rejection in pediatric heart transplant recipients.

BACKGROUND: Accumulating evidence suggests that immune-mediated injury is important in the development of rejection after heart transplantation. We hypothesized that pro-inflammatory cytokine expression would increase in biopsy samples that manifest cellular rejection and that this would correlate with the development and progression of transplant cellular rejection. METHODS: Children with heart transplants were prospectively enrolled from July 2004 to November 2005. Right ventricular endomyocardial biopsies were obtained during routine catheterization for rejection surveillance. Cellular rejection was graded using criteria established by the International Society for Heart and Lung Transplantation. RNA was extracted from biopsy samples and reverse transcription was used for complementary DNA synthesis. The cDNA product was evaluated by quantitative real-time polymerase chain reaction (PCR) to measure the following cytokines: interleukin (IL)-1beta, IL-6 and IL-18; tumor necrosis factor-alpha (TNF-alpha); and interferon-gamma (IFN-gamma). Normalized cytokine mRNA transcripts were correlated with cellular rejection scores and the presence of viral genome. RESULTS: Seventy-four children (mean age 9.6 +/- 5.5 years, range 0.2 to 20.5 years) were enrolled and 95 biopsies were obtained. None of the cytokines demonstrated a correlation with the cellular rejection score, even within individual patients for whom multiple, serial biopsy samples were studied. Eighteen biopsy samples were found to have parvovirus B19 genome present, but there was no correlation between cytokine levels and the presence of parvovirus. CONCLUSIONS: Cytokine transcripts in heart transplants do not correlate with cellular rejection. In addition, there is no correlation between cytokine transcripts and the presence of viral genome.

The efficacy of mitral valve surgery in children with dilated cardiomyopathy and severe mitral regurgitation.

Severe mitral regurgitation predicts poor outcomes in adults with left ventricular dysfunction. Frequently, adult patients now undergo initial mitral valve surgery instead of heart transplant. Pediatric data are limited. This study evaluates the efficacy of mitral valve surgery for severe mitral regurgitation in children with dilated cardiomyopathy. This is a single-institution experience in seven children (range, 0.5-10.9 years) with severe mitral regurgitation and dilated cardiomyopathy who underwent mitral valve surgery between January 1988 and February 2005, with follow-up to January 2006. Children with dilated cardiomyopathy had a depressed fractional shortening preoperatively (24.4% +/- 6.1%) that remained depressed (22.9% +/- 7.6%) 1.3 +/- 1.2 years after surgery (p = 0.50). Left ventricular end-diastolic (6.5 +/- 1.5 to 4.8 +/- 1.8 z-scores, p < 0.01) and end-systolic (6.8 +/- 1.5 to 5.5 +/- 2.1 z-scores, p < 0.05) dimensions improved. Hospitalization frequency had a median decrease of 6.0 hospitalizations per year (p < 0.02). Three patients were transplanted 0.2, 2.4, and 3.5 years after surgery. There was no perioperative mortality. Mitral valve surgery in children with dilated cardiomyopathy was performed safely and improved symptoms, stabilizing ventricular dysfunction in most patients. Mitral valve surgery should be considered prior to heart transplant in children with dilated cardiomyopathy and severe mitral regurgitation.

B-type natriuretic peptide is a sensitive screening test for acute rejection in pediatric heart transplant patients.

BACKGROUND: The utility of B-type natriuretic peptide (BNP) for detecting acute rejection (AR) is unclear. The purpose of our study was to evaluate BNP as a screening test for AR in pediatric heart transplant patients. METHODS: All endomyocardial biopsies (EMBs) with concurrent BNP levels from February 2004 through March 2007 at the study institution were reviewed and the association between BNP levels and acute rejection was assessed. RESULTS: Eighty-six patients underwent a total of 560 EMBs. The median age at EMB was 10.5 years (interquartile range [IQR] 3.7 to 15.4 years). There were 59 episodes of AR, 32 (54%) occurring at <1 year post-transplant. BNP levels were higher in patients with AR, median 387 pg/ml (IQR 125 to 931 pg/ml), compared with those without AR, median 66 pg/ml (IQR 37 to 148 pg/ml) (p < 0.001). The receiver operating characteristic (ROC) curve for BNP demonstrated an area under the curve (AUC) of 0.82 (95% confidence interval [CI] 0.76 to 0.88) (p < 0.001). A BNP level of 100 pg/ml corresponded to a sensitivity of 0.85 (95% CI 0.73 to 0.92) and a negative predictive value (NPV) of 0.97 (95% CI 0.95 to 0.99) for detecting AR. The ROC curve for patients at >1 year post-transplant demonstrated an AUC of 0.86 (95% CI 0.80 to 0.93) (p < 0.001), and a BNP level of 100 pg/ml corresponded to a sensitivity of 0.96 (95% CI 0.79 to 0.99) and NPV of 0.994 (95% CI 0.962 to 0.999) for detecting AR. CONCLUSIONS: BNP levels have a high sensitivity and NPV for evaluating AR in pediatric heart transplant patients. In patients >1 year post-transplant, a BNP level of <100 pg/ml correlates with a <1% chance of AR and may obviate the need for EMB in some cases.

Use of mechanical circulatory support in pediatric patients with acute cardiac graft rejection.

Patients suffering from acute cardiac graft rejection can die because of hemodynamic collapse while being treated with vigorous immunosuppressive therapies. There is little pediatric data on the use of mechanical circulatory support (MCS) in patients with acute cardiac graft rejection accompanied by hemodynamic instability. This report reviews our experience using MCS in patients with severe acute allograft rejection and cardiogenic shock. Between July 1995 and December 2006, 7 of 117 heart transplant recipients (6%) had MCS placed in 8 cases of acute graft rejection with hemodynamic instability. Devices used were BioMedicus (five), Thoratec (two), and extracorporeal membrane oxygenation machine (one). Mean age was 12 +/- 6.6 years. Median duration of support was 7.5 days (range, 3-28 days). Medical therapy applied included pulse steroids (eight), antithymocyte globulin (five), intravenous immunoglobulins (five), and plasmapheresis (five). Eighty-eight percent (seven of eight cases) weaned from MCS. Five patients weaned to recovery and two were bridged to retransplant. Five of the seven patients weaned (71%) were discharged home, all with normal left ventricular function. Median follow-up was 3.0 years (4.5 months to 3.5 years). One-year survival is 50% and 3 year survival is 38%. Mechanical circulatory support can be applied in patients with acute cardiac graft rejection causing hemodynamic instability with acceptable weaning and discharge rates. Unfortunately, late survival for this cohort remains poor.

Effect of body mass index on outcome in pediatric heart transplant patients.

BACKGROUND: Obesity and cachexia are risk factors for adverse outcomes in adult transplant patients. However, little is known about the effects of body mass index (BMI) on outcomes in pediatric heart transplant patients. METHODS: Patients > 2 years of age undergoing heart transplantation from 1985 to 2004 at our institution were included in this study. BMI was assessed at the time of transplant and at 1 year post-transplant. Long-term outcomes were assessed by weight group. RESULTS: The cohort included 105 patients with a mean age at transplant of 9.6 +/- 5.3 years. The mean BMI percentile at the time of transplant was 39 +/- 34, with 22 (21%) patients underweight (< 5th percentile) and 8 (8%) patients overweight (> or = 95th percentile). Among patients surviving to 1 year (n = 92), the mean BMI percentile increased to 57 +/- 33 (p < 0.05). Overall graft survival was decreased in patients underweight at transplant, mean 6.7 years (95% confidence interval [CI] 3.6 to 9.9), vs normal weight patients, mean 10.6 years (95% CI 8.8 to 12.4) (p < 0.05). Patients overweight at transplant did not have decreased graft survival. Neither low nor high BMI at 1 year post-transplant was associated with adverse outcomes. On multivariate analysis, being underweight at transplant was an independent predictor of decreased graft survival (p = 0.03). CONCLUSIONS: Weight gain was nearly universal post-transplant with only 4% of patients underweight at 1 year. In the small number of patients overweight at transplant, graft survival was similar to normal-weight patients. Conversely, being underweight at transplant was an independent predictor of decreased graft survival.

Symptom complex is associated with transplant coronary artery disease and sudden death/resuscitated sudden death in pediatric heart transplant recipients.

BACKGROUND: Transplant coronary artery disease (TCAD) is a common sequela of heart transplantation. Symptom complexes associated with TCAD have not been well described. The purpose of this study was to determine if somatic complaints are associated with TCAD in pediatric heart transplant recipients. METHODS: We reviewed the medical records of all patients who underwent heart transplantation at our institution from November 1984 to December 2000. TCAD was defined as any interval narrowing of coronary arteries by angiography since the previous study or at least 50% luminal obstruction of 1 or more coronary arteries by histologic examination of explanted or autopsied hearts. RESULTS: Ninety-nine patients received heart transplants, and follow-up data were available in 80. Sixty-six patients met study criteria. Complaints of abdominal (82%), chest (45%), abdominal and chest (27%), and arm (9%) pain were made by 22 (33%) of 66 patients, and TCAD was present in 27 (41%). Of the 22 patients with pain, TCAD was present in 18, for a positive predictive value of 82% (95% confidence interval [CI] 60%-95%). The relative risk of TCAD being present in patients with a history of pain was 4 times that of patients without pain (p < 0.001). Sudden death or resuscitated sudden death occurred in 15 (68%) of 22 patients with pain vs 4 (9%) of 44 without pain (p < 0.001). CONCLUSIONS: The symptom complex of abdominal, chest and/or arm pain is strongly associated with the presence of TCAD and sudden death or resuscitated sudden death in pediatric heart transplant recipients.