Sarah K. Clunie

Clinical Characterization of Left Ventricular Noncompaction in Children A Relatively Common Form of Cardiomyopathy

Background—Left ventricular noncompaction (LVNC) is a reportedly uncommon genetic disorder of endocardial morphogenesis with a reportedly high mortality rate. The purpose of this study was to identify the clinical characteristics of children with LVNC. Methods and Results—We retrospectively reviewed 36 children with LVNC evaluated at Texas Children’s Hospital (TCH) from January 1997 to December 2002. Five children had associated cardiac lesions. There were 16 girls and 20 boys. The median age at presentation was 90 days (range, 1 day to 17 years). The median duration of follow-up was 3.2 years (range, 0.5 to 12 years). Twenty-seven patients (75%) had ECG abnormalities, most commonly biventricular hypertrophy (10 patients, 28%). Both ventricles were involved in 8 patients (22%) and only the left ventricle in 28 patients (78%). Left ventricular systolic function was depressed in 30 patients (83%), with a median ejection fraction of 30% (range, 15% to 66%) at diagnosis. Nine patients presenting in the first year of life with depressed left ventricular contractility had a transient recovery of function; however, ejection fraction deteriorated later in life, at a median interval of 6.3years (range, 3 to 12 years). Two patients had an “undulating” phenotype from dilated to hypertrophic cardiomyopathy. Two patients (6%) were identified with an underlying G4.5 gene mutation. Five patients (14%) died during the study. Conclusions—LVNC does not have an invariably fatal course when diagnosed in the neonatal period. A significant number of patients have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an “undulating” phenotype.

Characterization of Left Ventricular Diastolic Function by Tissue Doppler Imaging and Clinical Status in Children With Hypertrophic Cardiomyopathy

Background—Conventional transmitral Doppler indices are unreliable in assessing clinical status in patients with hypertrophic cardiomyopathy (HCM) because they are affected by loading conditions. This study sought to determine whether tissue Doppler velocities are predictive of adverse clinical outcomes including death, cardiac arrest, ventricular tachycardia (VT), significant cardiac symptoms, and exercise capacity in children with HCM. Methods and Results—We studied 80 consecutive children (median age 12 years, median follow-up 26 months) evaluated at 1 hospital from January 1999 to August 2003 compared with 80 age- and gender-matched controls. Patients underwent echocardiography, ambulatory Holter monitoring, and upright exercise testing. Children with HCM had significantly decreased early diastolic tissue Doppler velocities at the lateral mitral (13.2 versus 19.3 cm/s), tricuspid (13.3 versus 16.3 cm/s), and septal (9.4 versus 13.5 cm/s) annuli compared with controls (P <0.001 for each comparison). By forward stepwise regression analysis, early transmitral left ventricular filling velocity (E)/septal Ea ratio predicted death, cardiac arrest, or VT (r =0.610, R2 =0.37, P <0.001). Peak oxygen consumption (&OV0312;O2) was most predictive of children who developed symptoms (r =0.427, R2 =0.182, P <0.001). Peak &OV0312;O2 correlated inversely with E/Ea septal ratio (r =−0.740, P <0.01). Conclusions—Transmitral E/septal Ea ratio predicts children with HCM who are at risk of adverse clinical outcomes including death, cardiac arrest, VT, and significant cardiac symptoms. Peak &OV0312;O2 correlated with peak exercise capacity in HCM patients.

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.

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.

Left ventricular non-compaction cardiomyopathy in children: characterisation of clinical status using tissue Doppler-derived indices of left ventricular diastolic relaxation

Background: Left ventricular non-compaction (LVNC) may manifest an undulating phenotype ranging from dilated to hypertrophic appearance. It is unknown whether tissue Doppler (TD) velocities can predict adverse clinical outcomes including death and need for transplantation in children with LVNC. Methods and results: 56 children (median age 4.5 years, median follow-up 26 months) with LVNC evaluated at one hospital from January 1999 to May 2004 were compared with 56 age/sex-matched controls. Children with LVNC had significantly decreased early diastolic TD velocities (Ea) at the lateral mitral (11.0 vs 17.0 cm/s) and septal (8.9 vs 11.0 cm/s) annuli compared with normal controls (p<0.001 for each comparison). Using receiver operator characteristic curves, the lateral mitral Ea velocity proved the most sensitive and specific predictor for meeting the primary end point (PEP) at 1 year after diagnosis (area under the curve = 0.888, SE = 0.048, 95% CI 0.775 to 0.956). A lateral mitral Ea cut-off velocity of 7.8 cm/s had a sensitivity of 87% and a specificity of 79% for the PEP. Freedom from death or transplantation was 85% at 1 year and 77% at 2 years. Conclusions: TD velocities are significantly reduced in patients with LVNC compared with normal controls. Reduced lateral mitral Ea velocity helps predict children with LVNC who are at risk of adverse clinical outcomes including death and need for cardiac transplantation.

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.

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.

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.

Long-term follow-up of arrhythmias in pediatric orthotopic heart transplant recipients: incidence and correlation with rejection

BACKGROUND Arrhythmias in adult orthotopic heart transplant (OHT) recipients are common and have been used as predictors of rejection. Because of the paucity of information in pediatric OHT recipients, the purpose of this study was to determine the incidence and correlation of arrhythmias with rejection or with coronary artery disease (CAD) in children. METHODS We retrospectively reviewed the records, electrocardiograms (ECGs), and 24-hour ambulatory ECGs of patients who underwent OHT from January 1984 to December 1999. We excluded arrhythmias occurring in the first 2 weeks after OHT. RESULTS Sixty-nine patients underwent OHT, received triple-immunosuppression therapy, were discharged home, and have been followed for a mean of 4.7 years (0.3-13 years). Each patient had an average of 10 ECGs and three 24-hour ECGs. Twenty-six patients had 33 arrhythmias: sinus bradycardia (n = 9), atrial tachycardia (n = 9), ventricular tachycardia (n = 3), and Wenckebach periodicity (n = 6). Sinus bradycardia was treated with theophylline in 8 patients, and 2 required pacemakers. Atrial tachycardias (atrial flutter in 4 patients and atrial ectopic tachycardia in 5) were treated with digoxin, propranolol, or procainamide. Ventricular tachycardia was treated with mexiletine, lidocaine, and amiodarone. There were 65 episodes of rejection, 20 of which were moderate/severe (> or =3B). Only Wenckebach was associated with the presence of either rejection or CAD (p < 0.05). CONCLUSIONS We noted clinically significant arrhythmias in 38% of the pediatric OHT recipients. Sinus bradycardia, atrial tachyarrhythmias, and ventricular tachycardia occurred with the same frequency. Only new-onset Wenckebach periodicity was noted in the presence of either CAD or rejection. No arrhythmia was of negative predictive value for rejection or CAD. From this data, we suggest that new-onset Wenckebach prompt evaluation for rejection or CAD.

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.