Right ventricular wall-motion changes after infant open heart surgery--a tissue Doppler study.

BACKGROUND: Right ventricular (RV) dysfunction is a well-recognized complication of cardiopulmonary bypass surgery (CPB) in adults. Infants and neonates may also be at high risk for this due to immature myocardium. Conventional assessment of RV function is just qualitative, but novel tissue Doppler echocardiographic (TDI) markers including peak systolic strain rate (SR) and isovolumic contraction acceleration (IVA) permit noninvasive quantitation of RV function. This study assessed myocardial velocities, IVA and SR in infants and neonates undergoing open heart surgery using TDI to study regional myocardial function perioperatively. METHODS: Transthoracic TDI data were obtained in the OR before and 24 hours post-CPB on 53 consecutive infants (age 0.39 ± 0.23 years). They were followed with TDI through hospital discharge. RESULTS: Mean CPB time was 87 ± 49 min (cross-clamp 52 ± 26 min). Peak systolic (STDI ) and diastolic myocardial velocities (ETDI , ATDI ), IVA, and peak SR were recorded in RV and LV from standard views for offline analysis. Postoperatively, LV systolic function and diastolic longitudinal function were unchanged or improved from baseline. LV radial velocities were increased postoperatively indicating adequate support. In contrast, RV longitudinal systolic and diastolic function was significantly diminished after CPB. RV changes persisted through hospital discharge. CONCLUSIONS: In infants and neonates, perioperative measurements of systolic and diastolic tissue Doppler parameters are feasible and revealed significant RV systolic and diastolic dysfunction post-CPB with preserved LV function. As such, TDI provides a sensitive tool to monitor the infant heart after CPB and may potentially be useful to assess different myocardial protection strategies.

Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by low-grade tumors of the central and peripheral nervous system. There is also an increased risk of developing malignant tumors. Glioblastoma is an uncommon, malignant tumor of children that is even less frequently observed in children with NF1. PROCEDURE: We performed a retrospective review of patients with NF1 and glioblastoma to determine specific clinical and pathologic indicators of overall prognosis. RESULTS: Five patients were identified from the CHB/DFCI database for whom pathologic and imaging studies were available. All pathologic specimens demonstrated vascular proliferation and necrosis. All samples stained positively for p53. Chromogenic in situ hybridization (CISH) for epidermal growth factor receptor (EGFR) copy numbers was increased, PTEN copy numbers were normal and the promoter of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene was unmethylated in the one patient evaluated. In the same time period, there were 56 patients without NF1 diagnosed with glioblastoma who were treated at our institution. Although the small sample size precludes formal statistical analysis, the 2-year survival of patients with NF1 is 60% with median overall survival of 9.25 years compared to non-NF1 patients with a 2-year survival of 25% and median overall survival 1.08 years. CONCLUSIONS: This study provides preliminary evidence that children with NF1 may be at risk for glioblastoma, but that these patients have an increased survival compared to children without NF1. Additional molecular studies will be required to determine if the pathogenesis of these tumors differs from glioblastoma in children without NF1.

Utility of chromosomal chromogenic in situ hybridization as an alternative to flow cytometry and cytogenetics in the diagnosis of early partial hydatidiform moles: a validation study.

OBJECTIVE: The introduction of p57 immunohistochemistry has aided the distinction between early complete moles (CMs) and hydropic abortus (HA), but no single technique has emerged for the distinction between early partial moles (PMs) and HA. Flow cytometry and cytogenetics have been used, but these require specialized equipment/expertise. The goal of this study is validation of chromosome in situ hybridization (CrISH), focusing on comparing the results to those obtained by cytogenetic methods. STUDY DESIGN: Archival paraffin blocks from molar and nonmolar gestations were retrieved. Sections were labeled with a chromosome 10 probe. Hybridization and visualization were performed using standard protocols. One hundred nuclei per sample were scored for the number ofsignals. RESULTS: Of 50 hydatidiform moles, 22 were PMs and 28 were CMs. The CMs showed 2 signals in 25 cases and 4 signals in 3 cases. The PMs showed 3 signals in 21 cases and 2 signals in 1 case. For the HAs there were 2 signals in 24 cases, and 1 case had 3 signals. Concordance between CrISH and flow cytometry studies for molar gestations was 95%. CONCLUSION: CrlSH is a highly effective adjunct in differentiating between PM and CM and between PM and HA. CrlSH is a simple, cost effective adjunct in evaluating molar gestations.

Global Left Ventricular Relaxation: A Useful Echocardiographic Marker of Heart Transplant Rejection and Recovery in Children.

BACKGROUND: Tissue Doppler velocities are impaired after heart transplantation and further diminished in acute rejection. METHODS: Left ventricular relaxation index (LVRI) was calculated as the sum of E' of the left ventricular lateral, septal and posterior walls divided by left ventricular posterior wall (LVPW) thinning (LVRI = E' lateral + E' septal + E' posterior/[systolic LVPW - diastolic LVPW/systolic LVPW]). On the basis of a prior study, LVRI > 0.8 was considered normal after transplantation. Serial LVRI measurements (n = 941) were analyzed in a total of 35 patients who underwent transplantation. The sensitivity and specificity of LVRI < 0.8 for detecting rejection were calculated. LVRI was compared at baseline, at diagnosis of rejection, and at recovery after rejection treatment for each patient. The potential role of ischemic graft time, pretransplantation waiting period, and pretransplantation diagnosis on LVRI recovery was also assessed. RESULTS: LVRI was low early after transplantation (mean, 0.69) normalizing (mean, 0.91) at a median of 39.6 days (range, 5-115 days) after transplantation. Fifteen episodes of rejection were seen in 11 patients. LVRI was lower at diagnosis of rejection compared with baseline (P = .0013). LVRI < 0.8 had 93.3% sensitivity (95% CI, 68%-99.8%) and 89.5% specificity (95% CI, 67%-99%) for detecting all rejection. LVRI recovered at a mean of 28.3 days after onset of treatment. No correlation was found to ischemic graft time, to pretransplantation waiting period, or to pretransplantation diagnosis. CONCLUSION: After the early posttransplantation period, serial measurements of LVRI appear to be a useful echocardiographic marker of heart transplantation rejection in children and of the effectiveness of rejection treatment. As such, this method may be of value in the ongoing clinical management of these difficult patients.

Hydrodynamic Assessment of Aortic Valves Prepared from Porcine Small Intestinal Submucosa.

Infants and children born with severe cardiac valve lesions have no effective long term treatment options since currently available tissue or mechanical prosthetic valves have sizing limitations and no avenue to accommodate the growth of the pediatric patient. Tissue engineered heart valves (TEHVs) which could provide for growth, self-repair, infection resistance, and long-term replacement could be an ideal solution. Porcine small intestinal submucosa (PSIS) has recently emerged as a potentially attractive bioscaffold for TEHVs. PSIS may possess the ability to recruit endogenous cardiovascular cells, leading to phenotypically-matched replacement tissue when the scaffold has completely degraded. Our group has successfully implanted custom-made PSIS valves in 4 infants with critical valve defects in whom standard bioprosthetic or mechanical valves were not an option. Short term clinical follow-up has been promising. However, no hydrodynamic data has been reported to date on these valves. The purpose of this study was to assess the functional effectiveness of tri-leaflet PSIS bioscaffolds in the aortic position compared to standard tri-leaflet porcine bioprosthetic valves. Hydrodynamic evaluation of acute PSIS function was conducted using a left heart simulator in our laboratory. Our results demonstrated similar flow and pressure profiles (p > 0.05) between the PSIS valves and the control valves. However, forward flow energy losses were found to be significantly greater (p < 0.05) in the PSIS valves compared to the controls possibly as a result of stiffer material properties of PSIS relative to glutaraldehyde-fixed porcine valve tissue. Our findings suggest that optimization of valve dimensions and shape may be important in accelerating de novo valve tissue growth and avoidance of long-term complications associated with higher energy losses (e.g. left ventricular hypertrophy). Furthermore, long term animal and clinical studies will be needed in order to conclusively address somatic growth potential of PSIS valves.

Extraction of pulmonary vascular compliance, pulmonary vascular resistance, and right ventricular work from single-pressure and Doppler flow measurements in children with pulmonary hypertension: a new method for evaluating reactivity: in vitro and clinical studies.

BACKGROUND: Current evaluation of pulmonary hypertension (PH) in children involves measurement of pulmonary vascular resistance (PVR); however, PVR neglects important pulsatile components. Pulmonary artery (PA) input impedance and ventricular power (VP) include mean and pulsatile effects and have shown promise as alternative measures of vascular function. Here we report the utility of pulsed-wave (PW) Doppler-measured instantaneous flow and pressure measurements for estimation of input impedance and VP and use this method to develop a novel parameter: reactivity in compliance. METHODS AND RESULTS: An in vitro model of the general pulmonary vasculature was used to obtain impedance and VP, measured by PW Doppler and a reference flow meter. The method was then tested in a preliminary clinical study in subjects with normal PA hemodynamics (n=4) and patients with PH undergoing reactivity evaluation (8 patients; 23 data points). In vitro results showed good agreement between the impedance spectra computed from both flow-measurement methods. Excellent correlation was seen in vitro between actual resistance and the zero-frequency (Z(o)) impedance value (r2=0.984). Excellent agreement was also found between Z(o) and PVR in the clinical measurements (y=1.075x+0.73; r=0.993). Furthermore, total VP and VP/cardiac output increased significantly with hypertension (128.73 to 365.91 mW and 2.42 to 6.69 mW x mL(-1) x s(-1), respectively). The first-harmonic value of impedance (Z1) was used as a measure of compliance reactivity; older patients exhibited markedly less compliance reactivity than did younger patients. CONCLUSIONS: Input impedance and VP calculated from Doppler measurements and a single-catheter pressure measurement provide comprehensive characterization of PH and reactivity.

Regional myocardial velocities and isovolumic contraction acceleration before and after device closure of atrial septal defects: a color tissue Doppler study.

BACKGROUND: The study analyzed the effect of atrial septal defect (ASD) device closure on regional wall motion in the right (RV) and left ventricles (LV) using color tissue Doppler imaging (TDI). Atrial septal defect closure results in acute volume unloading of the RV. For unknown reasons, some patients develop acute left-sided heart failure postintervention. METHODS: Color TDI was performed in 39 pediatric ASD and 75 age-matched controls. Regional wall motion in 5 LV and 1 RV segment were analyzed before, immediately after, and 24 hours after interventional ASD closure. Off-line postprocessing of echocardiographic data was used to determine myocardial velocities and acceleration during isovolumic contraction (IVA). Isovolumic contraction acceleration is the slope of the upstroke of the isovolumic contraction wave (IVA = peak velocity/acceleration time). RESULTS: At baseline, patients with ASD had significantly higher RV systolic velocities than controls. Isovolumic contraction acceleration was similar in patients with ASD and controls. In the catheterization laboratory postintervention, conventional function parameters remained stable but systolic myocardial velocities decreased significantly in all segments. Diastolic velocities fell in LV segments but not in the RV. In contrast to velocities, IVA was stable during ASD device closure. On follow-up at 24 hours, myocardial velocities had normalized. CONCLUSIONS: Device closure of ASD results to an acute transient decrease of regional myocardial velocities in the LV and RV, whereas the load-insensitive marker isovolumic acceleration remained stable. Therefore, the velocity changes may represent a response to altered left and right ventricular loading conditions. Color TDI is a sensitive tool to analyze ventricular mechanics.

Non-invasive detection of acute allograft rejection in children by tissue Doppler imaging: myocardial velocities and myocardial acceleration during isovolumic contraction.

BACKGROUND: In adults, an acute decrease of regional myocardial velocities is a sensitive marker of rejection. In children, velocities are more variable. A new marker, myocardial acceleration during isovolumic contraction (IVA), appears to be less age-dependent than myocardial velocities. This study therefore compared tissue Doppler (TDI)-derived velocities and IVA as potential rejection markers for children. METHODS: TDI was performed in 15 pediatric heart transplant recipients (age 8.0 +/- 3.6 years) during acute rejection and at baseline without rejection, 50 additional transplant children without rejection (7.8 +/- 5.9 years) and 30 age-matched healthy children (7.5 +/- 5.2 years). Color Doppler cine-loops of 3 cardiac cycles were stored as echocardiographic raw data. Using off-line post-processing, systolic (S) and diastolic (E) myocardial velocities and IVA were measured in 5 basal left ventricular segments. IVA is the peak isovolumic contraction wave velocity divided by acceleration time. RESULTS: Without rejection, transplant children had significantly lower diastolic velocities (basal lateral E 10.4 +/- 2.9 vs 11.9 +/- 2.6 cm/s; p < 0.001) and systolic velocities (S 5.6 +/- 1.4 vs 7.1 +/- 2.0 cm/s; p < 0.001) than normal age-matched controls, but IVA was similar (1.2 +/- 1.4 vs 1.3 +/- 0.5 m/s2). During rejection, all markers decreased significantly compared with age-matched normal control, the non-rejecting transplant group and individual baseline values. CONCLUSIONS: Regional myocardial velocities change significantly during acute allograft rejection in children. However, many children already have wall motion abnormalities at baseline, so results are often difficult to interpret. In contrast, isovolumic acceleration was normal without rejection and selectively decreased during the event. IVA is a promising non-invasive rejection marker for pediatric patients.

Double-orifice mitral valve with intact atrioventricular septum: an echocardiographic study with anatomic and functional considerations.

We identified 18 patients with double-orifice mitral valve (DOMV) and intact atrioventricular (AV) septum out of 40,179 echocardiographic studies performed between 1997 and 2002 at Children's Hospital, Denver, CO. In this study we describe (1) the anatomic characteristics of the DOMV in the absence of AV septal defect, (2) the function of the mitral valve by spectral and color Doppler flow mapping, and (3) associated lesions. The topographic location of the orifices in the leaflets suggests possible embryologic mechanisms of DOMV. In this series, DOMV was most commonly associated with left-sided obstructive lesions (in 39% of patients). Spectral and color Doppler interrogation demonstrated a normal flow profile in most cases; only 2 patients had significant mitral regurgitation or stenosis. Therefore, due to the uncertain natural history of this lesion and the potential need for endocarditis prophylaxis, careful imaging of the mitral valve is recommended, particularly in the presence of left-sided obstructive lesions.

Longitudinal motion of the atrioventricular annuli in children: reference values, growth related changes, and effects of right ventricular volume and pressure overload.

The goals of this study were to characterize normal patterns of longitudinal motion of atrioventricular annuli in the young, establish reference values and assess growth-related changes (n = 40). Sensitivity to changes in right ventricular volume and pressure load was assessed in patients with atrial septal defect (ASD) (n = 25) and with primary pulmonary hypertension (PPH) (n = 20). M-mode of the annuli were obtained from apical views. In healthy subjects, longitudinal %displacement decreased with growth, lateral tricuspid annulus had highest %displacement, velocity of annular descent did not change with growth, tricuspid lateral annulus had the highest velocity of descent, only ascent velocity of the lateral tricuspid annulus decreased with growth, velocities of ascent for the lateral annuli were similar and higher than the septum, and heart rate had no effect on parameters tested. In patients with ASD, the findings were an exaggerated normal pattern. In patients with PPH, %displacement and ascent velocities were blunted. Our results demonstrate the utility of this technique to assess annular dynamics in pediatric patients.

Mixed total anomalous pulmonary venous connection: Case report with bilateral venous collectors.

We present a case report of a 3-month-old boy with a mixed total anomalous pulmonary venous connection. The patient had situs solitus, small atrial septal defect, and 2 separate venous collectors. The right pulmonary veins drained through a right-sided venous collector into the coronary sinus. The left-sided pulmonary veins drained through the left-sided venous collector directly into the right superior vena cava. The use of the echocardiogram and Doppler color flow mapping to establish a detailed morphologic analysis, the sites of connection, and the presence of pulmonary venous obstructions as well as the value of this information to facilitate a successful surgical repair are discussed.

Preliminary experience with cardiac reconstruction using decellularized porcine extracellular matrix scaffold: human applications in congenital heart disease.

An ideal material for repair of congenitally malformed hearts would encourage tissue regeneration with growth potential. Decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) promotes tissue regeneration in animal models and noncardiac human applications. This retrospective review evaluates SIS-ECM for reconstruction of congenital heart defects. From June 2007 to May 2009, SIS-ECM patches were used in 43 operations on 40 patients aged 2 days to 13 years. In 16 cases, the SIS-ECM was used for pericardial closure. The SIS-ECM was used for cardiac or great vessel repair in 37 cases: atrial septal defect repair in 11, pulmonary arterioplasty in 10, right ventricular outflow tract patch in 6, pulmonary monocusp valve creation in 5, superior vena cava patch in 2 and aortoplasty in 2, valve leaflet augmentation in 2, and repair of unroofed coronary sinus in 1. Follow-up was complete. There were 5 deaths, all unrelated to the SIS-ECM. Mean follow-up was 7.85 months (0.5-24 months). No pericardial effusions or intracardiac or intravascular thromboses occurred related to the SIS-ECM. The patches did not shrink or calcify. Four of 5 monocusp valves were competent and none were stenotic. One patient who underwent tricuspid valve anterior leaflet augmentation with SIS-ECM required tricuspid valve replacement 4 months later for severe regurgitation following a catheter-based procedure. Explanted tissue showed resorption of the SIS-ECM, replacement with organized collagen, and re-endothelialization. Repair of congenital heart defects using SIS-ECM is feasible and safe. In valve reconstruction, this procedure shows potential for replacement by autologous tissue. Longer-term follow-up is required to assess the potential for growth.

Use of myocardial performance index in pediatric patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: The myocardial performance index (MPI) correlates with clinical status in adults with idiopathic pulmonary arterial (PA) hypertension (IPAH). This pediatric study used MPI to assess response to bosentan therapy. METHODS: The study included 12 children with IPAH and 12 healthy control subjects. MPI was correlated with catheterization data at initiation of bosentan and at a median follow-up of 9 months. Therapy responders were defined by a greater than 20% decrease in mean PA pressure. RESULTS: Right ventricular MPI for patients with IPAH was 0.64 +/- 0.30 versus 0.28 +/- 0.03 in control subjects (P < .01). It had a strong correlation with mean PA pressure (R = 0.94; P < .001). Right ventricular MPI decreased significantly in responders (range 20%-44%, mean 25%) with a 5% increase in nonresponders. CONCLUSIONS: Right ventricular MPI in pediatric IPAH correlates with mean PA pressure and response to therapy. This study suggests that this noninvasive Doppler index may be useful to follow up children with IPAH, particularly when tricuspid regurgitation data are insufficient.

Noninvasive Doppler tissue measurement of pulmonary artery compliance in children with pulmonary hypertension.

BACKGROUND: We have shown previously that input impedance of the pulmonary vasculature provides a comprehensive characterization of right ventricular afterload by including compliance. However, impedance-based compliance assessment requires invasive measurements. Here, we develop and validate a noninvasive method to measure pulmonary artery (PA) compliance using ultrasound color M-mode (CMM) Doppler tissue imaging (DTI). METHODS: Dynamic compliance (C(dyn)) of the PA was obtained from CMM DTI and continuous wave Doppler measurement of the tricuspid regurgitant velocity. C(dyn) was calculated as: [(D(s) - D(d))/(D(d) x P(s))] x 10(4); where D(s) = systolic diameter, D(d) = diastolic diameter, and P(s) = systolic pressure. The method was validated both in vitro and in 13 patients in the catheterization laboratory, and then tested on 27 pediatric patients with pulmonary hypertension, with comparison with 10 age-matched control subjects. C(dyn) was also measured in an additional 13 patients undergoing reactivity studies. RESULTS: Instantaneous diameter measured using CMM DTI agreed well with intravascular ultrasound measurements in the in vitro models. Clinically, C(dyn) calculated by CMM DTI agreed with C(dyn) calculated using invasive techniques (23.4 +/- 16.8 vs 29.1 +/- 20.6%/100 mm Hg; P = not significant). Patients with pulmonary hypertension had significantly lower peak wall velocity values and lower C(dyn) values than control subjects (P < .01). C(dyn) values followed an exponentially decaying relationship with PA pressure, indicating the nonlinear stress-strain behavior of these arteries. Reactivity in C(dyn) agreed with reactivity measured using impedance techniques. CONCLUSION: The C(dyn) method provides a noninvasive means of assessing PA compliance and should be useful as an additional measure of vascular reactivity subsequent to pulmonary vascular resistance in patients with pulmonary hypertension.

Altered ventricular mechanics in cardiac allografts: a tissue Doppler study in 30 children without prior rejection events.

BACKGROUND: Tissue Doppler imaging (TDI), a non-invasive echocardiography technique, permits quantitative analysis of the regional distribution pattern of myocardial velocities. During normal childhood development, regional function changes markedly, including an increasing predominance of longitudinal velocities. This study analyzed the impact of heart transplantation on ventricular mechanics in growing children. METHODS: TDI was performed in 30 pediatric heart transplant recipients (7.1 +/- 6.2 years) and 32 age-matched healthy children (6.8 +/- 5.4 years). Patients had no rejection history and were 3.1 years (median) post-transplant. Color TDI images from apical and parasternal views were stored as echocardiographic raw data. Off-line analysis was used to measure peak systolic and diastolic myocardial velocities in 6 basal cardiac segments for longitudinal (anterior, inferior, lateral, septal, right ventricle) and radial velocities (posterior). Isovolumic acceleration, a load-insensitive function marker, was determined as slope of the upstroke of the isovolumic contraction wave. Multiple regression modeling was used for statistics. RESULTS: Systolic myocardial velocities still increased with age after transplantation, but the velocity distribution pattern was changed. In transplanted hearts, left ventricular longitudinal velocities were lower and radial velocities were higher than in the controls, but isovolumic acceleration was similar. In the right ventricle, longitudinal velocities and isovolumic acceleration were significantly decreased after transplantation. Wall motion abnormalities were present in 50% of patients. CONCLUSIONS: Regional wall motion analysis shows significant alterations of the fundamental biomechanical pump function of the left ventricle after heart transplantation in children, with a shift from longitudinal to radial fibers and depressed right ventricular wall motion. This may have important implications for the long-term graft function required in children.