Russel Hirsch

Cardiac troponin I in pediatrics: Normal values and potential use in the assessment of cardiac injury

OBJECTIVE To establish normal values and determine the impact of congenital or acquired heart disease on serum cardiac troponin I (cTnI). METHODS Concentrations of cTnI were measured in two groups of children. Group A represented ambulatory pediatric patients with no apparent cardiac disease (n = 120) and patients in stable condition with known congenital or acquired cardiac abnormalities (n = 96); group B was composed of patients admitted to intensive care units with normal echocardiograms (n = 16), with abnormal echocardiograms (n = 36), and those with blunt chest trauma who were thought to have cardiac contusions (n = 7). RESULTS The cTnI concentrations were generally less than 2.0 ng/ml in group A and frequently below the level of detection for the assay (1.5 ng/ml). There was no statistical difference between the two outpatient subgroups (p = 0.66). Nine intensive care patients had cTnI values greater than 2.0 ng/ml. Six of these patients, all with abnormal echocardiograms, had values less than 7.7 ng/ml. All improved and had subsequent normal cTnI concentrations. None of the three remaining patients (two with systemic illness (trauma and sepsis) and one with severe pulmonary hypertension), all with values greater than 8.0 ng/ml, survived. Three of the four patients with high likelihood of cardiac contusion had cTnI concentrations greater than 2.0 ng/ml (including one patient who died). CONCLUSIONS Cardiac troponin-I values are generally not elevated in children with stable cardiac disease or general pediatric conditions. In the context of severe acute illness, significant elevation of cTnI may be an indicator of poor outcome. Elevation of cTnI may also have diagnostic value in cases when cardiac contusion is suspected.

Adverse event rates in congenital cardiac catheterization — A multi-center experience†

Objectives: To describe case mix variation among institutions, and report adverse event rates in congenital cardiac catheterization by case type. Background: Reported adverse event rates for patients with congenital heart disease undergoing cardiac catheterization vary considerably, due to non‐comparable standards of data inclusion, and highly variable case mix. Methods: The Congenital Cardiac Catheterization Outcomes Project (C3PO) has been capturing case characteristics and adverse events (AE) for all cardiac catheterizations performed at six pediatric institutions. Validity and completeness of data were independently audited. Results: Between 2/1/07 and 4/30/08, 3855 cases (670 biopsy, 1037 diagnostic, and 2148 interventional) were recorded, median number of cases per site 480 (308 to 1526). General anesthesia was used in 70% of cases (28 to 99%), and 22% of cases (15 to 26%) were non‐electively or emergently performed. Three institutions performed a higher proportion of interventions during a case, 72 to 77% compared to 56 to 58%. The median rate of AE reported per institution was 16%, ranging from 5 to 18%. For interventional cases the median rate of AE reported per institution was 19% (7 to 25%) compared to 10% for diagnostic cases (6 to 16%). The incidence of AE was significantly higher for interventional compared to diagnostic cases (20% vs 10%, p<0.001), as was the incidence of higher severity AE (9% vs 5%, p<0.001). Adverse events in biopsy cases were uncommon. Conclusions: In this multi‐institutional cohort, the incidence of AE is higher among interventional compared to diagnostic cases, and is very low among biopsy cases. Equitable comparisons among institutions will require the development and application of risk adjustment methods.

Catheterization for Congenital Heart Disease Adjustment for Risk Method (CHARM)

OBJECTIVES This study sought to develop a method to adjust for case mix complexity in catheterization for congenital heart disease to allow equitable comparisons of adverse event (AE) rates. BACKGROUND The C3PO (Congenital Cardiac Catheterization Project on Outcomes) has been prospectively collecting data using a Web-based data entry tool on all catheterization cases at 8 pediatric institutions since 2007. METHODS A multivariable logistic regression model with high-severity AE outcome was built using a random sample of 75% of cases in the multicenter cohort; the models were assessed in the remaining 25%. Model discrimination was assessed by the C-statistic and calibration with Hosmer-Lemeshow test. The final models were used to calculate standardized AE ratios. RESULTS Between August 2007 and December 2009, 9,362 cases were recorded at 8 pediatric institutions of which high-severity events occurred in 454 cases (5%). Assessment of empirical data yielded 4 independent indicators of hemodynamic vulnerability. Final multivariable models included procedure type risk category (odds ratios [OR] for category: 2 = 2.4, 3 = 4.9, 4 = 7.6, all p < 0.001), number of hemodynamic indicators (OR for 1 indicator = 1.5, ≥2 = 1.8, p = 0.005 and p < 0.001), and age <1 year (OR: 1.3, p = 0.04), C-statistic 0.737, and Hosmer-Lemeshow test p = 0.74. Models performed well in the validation dataset, C-statistic 0.734. Institutional event rates ranged from 1.91% to 7.37% and standardized AE ratios ranged from 0.61 to 1.41. CONCLUSIONS Using CHARM (Catheterization for Congenital Heart Disease Adjustment for Risk Method) to adjust for case mix complexity should allow comparisons of AE among institutions performing catheterization for congenital heart disease.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Procedure-Type Risk Categories for Pediatric and Congenital Cardiac Catheterization

Background— The Congenital Cardiac Catheterization Project on Outcomes (C3PO) was established to develop outcome assessment methods for pediatric catheterization. Methods and Results— Six sites have been recording demographic, procedural and immediate outcome data on all cases, using a web-based system since February 2007. A sample of data was independently audited for validity and data completeness. In 2006, participants categorized 84 procedure types into 6 categories by anticipated risk of an adverse event (AE). Consensus and empirical methods were used to determine final procedure risk categories, based on the outcomes: any AE (level 1 to 5); AE level 3, 4, or 5; and death or life-threatening event (level 4 or 5). The final models were then evaluated for validity in a prospectively collected data set between May 2008 and December 31, 2009. Between February 2007 and April 2008, 3756 cases were recorded, 558 (14.9%) with any AE; 226 (6.0%) level 3, 4, or 5; and 73 (1.9%) level 4 or 5. General estimating equations models using 6 consensus-based risk categories were moderately predictive of AE occurrence (c-statistics: 0.644, 0.664, and 0.707). The participant panel made adjustments based on the collected empirical data supported by clinical judgment. These decisions yielded 4 procedure risk categories; the final models had improved discrimination, with c-statistics of 0.699, 0.725, and 0.765. Similar discrimination was observed in the performance data set (n=7043), with c-statistics of 0.672, 0.708, and 0.721. Conclusions— Procedure-type risk categories are associated with different complication rates in our data set and could be an important variable in risk adjustment models for pediatric catheterization.

Patterns and Potential Value of Cardiac Troponin I Elevations After Pediatric Cardiac Operations

BACKGROUND Perioperative myocardial injury is a major determinant of postoperative cardiac dysfunction for congenital heart disease, but its assessment during this period is difficult. The objective of this study was to determine the suitability of using postoperative serum concentrations of cardiac troponin I (cTnI) for this purpose. METHODS Cardiac troponin I levels were measured serially in the serum of patients undergoing uncomplicated repairs of atrial septal defect (n = 23), ventricular septal defect (n = 16) or tetralogy of Fallot (n = 16). The concentrations were correlated with intraoperative parameters (cardiopulmonary bypass time, aortic cross-clamp time, and cardiac bypass temperature), and postoperative parameters (magnitude of inotropic support, duration of intubation, and postoperative intensive care and hospital stay). RESULTS Postoperative absolute cTnI levels were lesion specific, with a pattern of increase and decrease similar for each lesion. For the total cohort, significant correlations between postoperative cTnI levels at all times (r = 0.43 to 0.83, p < 0.05) until 72 hours were noted for all parameters, except for cardiac bypass temperature. When evaluated as individual procedure groups, no significant relationships were noted in the atrial septal defect group, whereas postoperative cTnI levels were more strongly correlated with all intraoperative and postoperative parameters in the ventricular septal defect group than in the tetralogy of Fallot group. CONCLUSIONS This study suggests that cTnI values immediately after operation reflect the extent of myocardial damage from both incisional injury and intraoperative factors. Cardiac tropinin I levels in the first hours after operation for congenital heart disease are a potentially useful prognostic indicator for difficulty of recovery.

Transplant coronary artery disease in pediatric heart transplant recipients.

BACKGROUND Transplant coronary artery disease (TxCAD) contributes to a large percentage of late morbidity and mortality among adult heart transplant recipients. Intracoronary ultrasound (ICUS) is a sensitive tool in the diagnosis of TxCAD in adult patients and has allowed analysis of factors contributing to disease development. Experience with ICUS in pediatrics, however, has been limited. By using ICUS we sought to determine the overall prevalence of TxCAD in pediatrics and to characterize factors associated with its development in this population. METHODS Eighty-six studies were performed in 51 pediatric patients a median of 3.4 years after heart transplantation. Evaluation included angiography and ICUS in 83 and angiography alone in 3 studies. Donor and recipient characteristics were obtained. The ICUS images were analyzed for intimal thickening and compared with coronary angiograms. The presence of any intimal thickening on ICUS was considered TxCAD. An intimal index and point of maximal intimal thickening (MIT) were measured. Vessel disease was graded 0 to 4 based on these results. Four patients had evidence of vasculopathy by angiography, whereas 32 patients (63%) had evidence of intimal proliferation by ICUS. Grade 2 or greater disease was present in 19 (37%) patients. A positive correlation was found when comparing time from transplant with intimal index and MIT (p < 0.001). No other factors were found to predict the development of disease. The overall prevalence of disease was 74% in patients studied at least 5 years after transplant. Intracoronary ultrasound can be performed safely in pediatric patients. Transplant coronary artery disease is common in infants and children after heart transplantation, although its prevalence appears to be less than in adult recipients at similar time intervals. We found no factor other than time from transplant was associated with development of disease.

Cardiac transplantation for pediatric restrictive cardiomyopathy: presentation, evaluation, and short-term outcome

BACKGROUND Because of the poor prognosis of pediatric restrictive cardiomyopathy, transplantation has been proposed as the treatment of choice for this disease. METHODS We reviewed our experience with the presentation, evaluation, and short-term outcome in 8 pediatric patients with restrictive cardiomyopathy referred for transplantation. Potential reversibility of elevation in pulmonary vascular resistance was tested before transplantation with nitroprusside and nitric oxide, with follow-up cardiac catheterization performed 6 to 12 months after transplantation. RESULTS The mean age of diagnosis of restrictive cardiomyopathy was 6.3 years and the mean interval from diagnosis to referral for transplantation was 3.6 years. Elevation of pulmonary vascular resistance was common and tended to progress with longer follow-up. Three of the 8 patients had pulmonary vascular resistance indices greater than 10 Woods unit/m(2) and transpulmonary gradients greater than 20 mm Hg. The administration of nitroprusside and nitric oxide reversed elevated pulmonary resistance and transpulmonary gradients in all patients. Nitric oxide successfully reversed pulmonary vascular resistance in patients unresponsive to nitroprusside. All patients underwent successful transplantation and follow-up catheterization revealed normal pulmonary hemodynamics in each patient. CONCLUSIONS Pediatric restrictive cardiomyopathy can be associated with marked elevation in the pulmonary vascular resistance, which may contribute to the poor prognosis in these patients and potentially make cardiac transplantation problematic. Orthotopic cardiac transplantation can be successfully performed in patients who demonstrate reversibility of pulmonary vascular resistance. Nitric oxide appears to be the best agent to demonstrate reversibility of pulmonary resistance in these patients.

Prediction and perinatal management of severely restrictive atrial septum in fetuses with critical left heart obstruction: Clinical experience using pulmonary venous Doppler analysis

OBJECTIVE Up to 20% of fetuses with critical left heart obstructive lesions have highly restrictive or intact atrial septae. Although this condition is generally tolerated in utero, severe hypoxemia requiring emergency atrial septostomy often develops in newborns with restrictive atrial septum. We have reported that a pulmonary venous Doppler forward/reverse time-velocity integral ratio less than 5 is highly predictive of the need for emergency atrial septostomy. We reviewed our subsequent experience using fetal pulmonary venous Doppler patterns to identify and manage fetuses with critical left heart obstruction and suspected restrictive atrial septum. METHODS A retrospective review of neonates with a prenatal diagnosis of critical left heart obstruction was performed. Fetal restrictive atrial septum was defined as a small/absent interatrial shunt on 2-dimensional imaging and a mean forward/reverse time-velocity integral ratio of 5 or less. Available serial pulmonary venous Doppler data were reviewed. The primary outcome was postnatal confirmation of restrictive atrial septum or severe left atrial hypertension. RESULTS Eight of 39 infants had a forward/reverse time-velocity integral ratio of 5 or less. A restrictive atrial septum was confirmed postnatally in 6 of 8 infants. Overall, a forward/reverse time-velocity integral ratio of 5 or less had a sensitivity of 100% and specificity of 94% for emergency atrial septostomy. Lowering the cutoff value to 3 or less would have eliminated false-positive diagnoses in the current series. Serial data demonstrated that late second trimester values did not change in later gestation with respect to either threshold in 30 of 32 fetuses. CONCLUSIONS In the fetus with critical left heart obstruction, a threshold forward/reverse time-velocity integral ratio of 3 or less optimizes specificity for predicting emergency atrial septostomy. Most late second trimester values will not change over time with regard to threshold levels.

Pulmonary Arterial Hypertension in Pediatric Patients with Hematopoietic Stem Cell Transplant–Associated Thrombotic Microangiopathy

Pulmonary arterial hypertension (PAH) is rarely included in the differential diagnosis of cardiorespiratory failure after pediatric hematopoietic stem cell transplant (HSCT) as the clinical presentation is nonspecific and may mimic other etiologies. The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion. We describe 5 children diagnosed with PAH after allogeneic HSCT. All 5 patients had prolonged clinical signs of transplantation-associated thrombotic microangiopathy (TA-TMA) when they presented with hypoxemic respiratory failure and evidence of PAH. Four of the 5 patients had echocardiographic evidence of PAH, and 1 patient was diagnosed with PAH only on autopsy. PAH was diagnosed a median of 76 days (range, 56-101 days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy. Three of the 4 deceased patients had an autopsy performed, demonstrating severe pulmonary vascular disease consistent with TA-TMA and severe PAH. We conclude that TA-TMA can be associated with significant pulmonary vascular injury presenting as hypoxemic respiratory failure with PAH after HSCT. Pediatric patients with unexplained hypoxemia after HSCT should be evaluated for both transplantation complications, TA-TMA and PAH, accordingly.