Sitaram M. Emani

Rapid-Response Extracorporeal Membrane Oxygenation to Support Cardiopulmonary Resuscitation in Children With Cardiac Disease

Background— Survival of children with in-hospital cardiac arrest that does not respond to conventional cardiopulmonary resuscitation (CPR) is poor. We report on survival and early neurological outcomes of children with heart disease supported with rapid-response extracorporeal membrane oxygenation (ECMO) to aid cardiopulmonary resuscitation (ECPR). Methods and Results— Children with heart disease supported with ECPR were identified from our ECMO database. Demographic, CPR, and ECMO details associated with mortality were evaluated using multivariable logistic regression. Pediatric overall performance category and pediatric cerebral performance category scores were assigned to ECPR survivors to assess neurological outcomes. There were 180 ECPR runs in 172 patients. Eighty-eight patients (51%) survived to discharge. Survival in patients who underwent ECPR after cardiac surgery (54%) did not differ from nonsurgical patients (46%). Survival did not vary by cardiac diagnosis and CPR duration did not differ between survivors and nonsurvivors. Factors associated with mortality included noncardiac structural or chromosomal abnormalities (OR, 3.2; 95% CI, 1.3–7.9), use of blood-primed ECMO circuit (OR, 7.1; 95% CI, 1.4–36), and arterial pH <7.00 after ECMO deployment (OR, 6.0; 95% CI, 2.1–17.4). Development of end-organ injury on ECMO and longer ECMO duration were associated with increased mortality. Of pediatric overall performance category/pediatric cerebral performance category scores assigned to survivors, 75% had scores ≤2, indicating no to mild neurological injury. Conclusions— ECPR may promote survival in children with cardiac disease experiencing cardiac arrest unresponsive to conventional CPR with favorable early neurological outcomes. CPR duration was not associated with mortality, whereas patients with metabolic acidosis and noncardiac structural or chromosomal anomalies had higher mortality.

In vivo monitoring of function of autologous engineered pulmonary valve

OBJECTIVES Clinical translation of tissue-engineered heart valves requires valve competency and lack of stenosis in the short and long term. Early studies of engineered valves showed promise, although lacked complete definition of valve function. Building on prior experiments, we sought to define the in vivo changes in structure and function of autologous engineered pulmonary valved conduits. METHODS Mesenchymal stem cells were isolated from neonatal sheep bone marrow and seeded onto a bioresorbable scaffold. After 4 weeks of culture, valved conduits were implanted. Valve function, cusp, and conduit dimensions were evaluated at implantation (echocardiography), at the experimental midpoint (magnetic resonance imaging), and at explant, at 1 day, and 1, 6, 12, or 20 weeks postoperatively (direct measurement, echocardiography). Histologic evaluation was performed. RESULTS Nineteen animals underwent autologous tissue-engineered valved conduit replacement. At implantation, valved conduit function was excellent; maximum transvalvular pressure gradient by Doppler echocardiography was 17 mm Hg; most valved conduits showed trivial pulmonary regurgitation. At 6 postoperative weeks, valve cusps appeared less mobile; pulmonary regurgitation was mild to moderate. At 12 weeks or more, valved conduit cusps were increasingly attenuated and regurgitant. Valved conduit diameter remained unchanged over 20 weeks. Dimensional measurements by magnetic resonance imaging correlated with direct measurement at explant. CONCLUSIONS We demonstrate autologous engineered tissue valved conduits that function well at implantation, with subsequent monitoring of dimensions and function in real time by magnetic resonance imaging. In vivo valves undergo structural and functional remodeling without stenosis, but with worsening pulmonary regurgitation after 6 weeks. Insights into mechanisms of in vivo remodeling are valuable for future iterations of engineered heart valves.

Cardiac Gene Delivery With Cardiopulmonary Bypass

Background—Cardiac gene therapy offers the possibility of enhancing myocardial performance in the compromised heart. However, current gene delivery techniques have limited myocardial transgene expression and pose the risk of extracardiac expression. Isolation of the coronary circulation during cardiac surgery may allow for more efficient and cardiac-selective gene delivery in a clinically relevant model. Methods and Results—Neonatal piglets (3 kg) underwent a median sternotomy and cardiopulmonary bypass, followed by aortic cross-clamping with 30 minutes of cardioplegic arrest. Adenoviral vectors containing transgenes for either &bgr;-galactosidase (adeno-&bgr;-gal, n=11) or the human &bgr;2-adrenergic receptor (adeno-&bgr;2-AR, n=15) were administered through the cardioplegia cannula immediately after arrest and were allowed to dwell in the coronary circulation during the cross-clamp period. After 1 week, the animals were killed, and their heart, lungs, and liver were excised and examined for gene expression. Analysis of &bgr;-galactosidase staining revealed transmural myocardial gene expression among animals receiving adeno-&bgr;-gal. No marker gene expression was detected in liver or lung tissue. &bgr;-AR density in the left ventricle after adeno-&bgr;2-AR delivery was 396±85% of levels in control animals (P <0.01). Animals receiving adeno-&bgr;2-AR and control animals demonstrated similar &bgr;-AR density in both the liver (114±8% versus 100±9%, P =NS) and lung (114±7% versus 100±9%, P =NS). There was no evidence of cardiac inflammation. Conclusions—By using cardiopulmonary bypass and cardioplegic arrest, intracoronary delivery of adenoviral vectors resulted in efficient myocardial uptake and expression. Undetectable transgene expression in liver or lung tissue suggests cardiac-selective expression.

Staged Left Ventricular Recruitment After Single-Ventricle Palliation in Patients With Borderline Left Heart Hypoplasia

OBJECTIVES The goal of this study was to review results of a novel management strategy intended to rehabilitate the left heart (LH) in patients with LH hypoplasia who have undergone single-ventricle palliation (SVP). BACKGROUND Management of patients with hypoplastic LH syndrome and borderline left ventricle (LV) involves 2 options: SVP or biventricular repair. We hypothesized that staged LV recruitment and biventricular conversion may be achieved after SVP by using a strategy consisting of relief of inflow and outflow tract obstructions, resection of endocardial fibroelastosis, and promotion of flow through the LV. METHODS Patients with hypoplastic LH and borderline LV who underwent traditional SVP (n = 34) or staged LV recruitment (n = 34) between 1995 and 2010 were retrospectively analyzed and compared with a control SVP group. RESULTS Mean initial z-scores for LH structures before stage 1 SVP were not significantly different between groups. Mortality occurred in 4 of 34 patients after LV recruitment and in 7 of 34 after traditional SVP. LH dimension z-scores increased significantly over time after LV recruitment, whereas they declined after traditional SVP, with significant interaction between stage of palliation and treatment group. Restriction of the atrial septum (conducted in 19 of 34 patients) was the only predictor of increase in left ventricular end-diastolic volume (p < 0.001). Native biventricular circulation was achieved in 12 patients after staged LV recruitment; all of these patients had restriction at the atrial septum. CONCLUSIONS In these patients with borderline LH disease who underwent SVP, it is possible to increase LH dimensions by using an LV recruitment strategy. In a subset of patients, this strategy allowed establishment of biventricular circulation.

Primary left ventricular rehabilitation is effective in maintaining two-ventricle physiology in the borderline left heart

OBJECTIVE Borderline left heart disease is characterized by left heart obstructive lesions (coarctation, aortic and mitral stenoses, left ventricular hypoplasia) and endocardial fibroelastosis. The multilevel obstruction and impaired left ventricular systolic and diastolic function contribute to failure of biventricular circulation. We studied the effects of left ventricular rehabilitation--endocardial fibroelastosis resection with mitral or aortic valvuloplasty--on left ventricular function and clinical outcomes. METHODS All patients with borderline left heart structures and endocardial fibroelastosis who underwent a primary left ventricular rehabilitation procedure were retrospectively analyzed to determine operative mortality, reintervention rates, and hemodynamic status. Left heart dimensions and hemodynamics were recorded from preoperative and postoperative echocardiogram and cardiac catheterization. Postoperative left atrial pressure was obtained from the intracardiac line early after left ventricular rehabilitation. Preoperative and postoperative values were compared by paired t test. RESULTS Between 1999 and 2008, 9 patients with endocardial fibroelastosis and borderline left heart disease underwent left ventricular rehabilitation at a median age of 5.6 months (range, 1-38 months). There was no operative mortality, and at a median follow-up of 25 months (6 months to 10 years) there was 1 death from noncardiac causes and 2 patients required reoperations. Significant increases in ejection fraction and left ventricular end-diastolic volume were observed, whereas left atrial pressure and right ventricular/left ventricular pressure ratios decreased postoperatively. CONCLUSION In patients with borderline left hearts, primary left ventricular rehabilitation with endocardial fibroelastosis resection and mitral and aortic valvuloplasty results in improved left ventricular systolic and diastolic performance and decreased right ventricular pressures. This approach may provide an alternative to single-ventricle management in this difficult patient group.

Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients.

Background— Fetal aortic valvuloplasty can be performed for severe midgestation aortic stenosis in an attempt to prevent progression to hypoplastic left heart syndrome (HLHS). A subset of patients has achieved a biventricular (BV) circulation after fetal aortic valvuloplasty. The postnatal outcomes and survival of the BV patients, in comparison with those managed as HLHS, have not been reported. Methods and Results— We included 100 patients who underwent fetal aortic valvuloplasty for severe midgestation aortic stenosis with evolving HLHS from March 2000 to January 2013. Patients were categorized based on postnatal management as BV or HLHS. Clinical records were reviewed. Eighty-eight fetuses were live-born, and 38 had a BV circulation (31 from birth, 7 converted after initial univentricular palliation). Left-sided structures, namely aortic and mitral valve sizes and left ventricular volume, were significantly larger in the BV group at the time of birth ( P <0.01). After a median follow-up of 5.4 years, freedom from cardiac death among all BV patients was 96±4% at 5 years and 84±12% at 10 years, which was better than HLHS patients (log-rank P =0.04). There was no cardiac mortality in patients with a BV circulation from birth. All but 1 of the BV patients required postnatal intervention; 42% underwent aortic or mitral valve replacement. On the most recent echocardiogram, the median left ventricular end-diastolic volume z score was +1.7 (range, −1.3 to +8.2), and 80% had normal ejection fraction. Conclusions— Short- and intermediate-term survival among patients who underwent fetal aortic valvuloplasty and achieved a BV circulation postnatally is encouraging. However, morbidity still exists, and ongoing assessment is warranted. # CLINICAL PERSPECTIVE {#article-title-39}Background— Fetal aortic valvuloplasty can be performed for severe midgestation aortic stenosis in an attempt to prevent progression to hypoplastic left heart syndrome (HLHS). A subset of patients has achieved a biventricular (BV) circulation after fetal aortic valvuloplasty. The postnatal outcomes and survival of the BV patients, in comparison with those managed as HLHS, have not been reported. Methods and Results— We included 100 patients who underwent fetal aortic valvuloplasty for severe midgestation aortic stenosis with evolving HLHS from March 2000 to January 2013. Patients were categorized based on postnatal management as BV or HLHS. Clinical records were reviewed. Eighty-eight fetuses were live-born, and 38 had a BV circulation (31 from birth, 7 converted after initial univentricular palliation). Left-sided structures, namely aortic and mitral valve sizes and left ventricular volume, were significantly larger in the BV group at the time of birth (P<0.01). After a median follow-up of 5.4 years, freedom from cardiac death among all BV patients was 96±4% at 5 years and 84±12% at 10 years, which was better than HLHS patients (log-rank P=0.04). There was no cardiac mortality in patients with a BV circulation from birth. All but 1 of the BV patients required postnatal intervention; 42% underwent aortic or mitral valve replacement. On the most recent echocardiogram, the median left ventricular end-diastolic volume z score was +1.7 (range, −1.3 to +8.2), and 80% had normal ejection fraction. Conclusions— Short- and intermediate-term survival among patients who underwent fetal aortic valvuloplasty and achieved a BV circulation postnatally is encouraging. However, morbidity still exists, and ongoing assessment is warranted.

Pulmonary Valve Replacement Function in Adolescents: A Comparison of Bioprosthetic Valves and Homograft Conduits

BACKGROUND Data comparing function and reintervention rates of various pulmonary valve replacements in adolescents are sparse. New transcatheter therapies-including transcatheter pulmonary valves-have been developed, and their utilization could be justified by these data. METHODS We performed a retrospective review that included baseline and operative data with cross-sectional follow-up on adolescents aged 10 to 21 years who underwent pulmonary valve replacement (n=254). We compared homograft conduits (n=84) with bioprosthetic pulmonary valves (n=170) in terms of freedom from valve dysfunction--right ventricular outflow tract obstruction greater than 50 mm Hg, or moderate or greater pulmonary regurgitation--and reintervention. RESULTS Median follow-up duration was 4.4 years and was longer in the homograft cohort. Freedom from valvar dysfunction was 72%±4% at 5 years and 48%±8% at 10 years. Freedom from right ventricular outflow tract reintervention was 90%±3% at 5 years, 67%±5% at 10 years, and 47%±8% at 15 years. No differences existed for dysfunction or reintervention between the homograft and bioprosthetic valve cohorts. Shorter freedom from dysfunction was associated with younger age, smaller implanted valve Z-score, valve replacement after prior homograft, and higher preoperative right ventricular outflow tract (RVOT) gradient. Shorter freedom from reintervention was associated with younger age, smaller implanted valve Z-score, and more recent valve implant. CONCLUSIONS Adolescents represent an important age group as an increasing number are undergoing pulmonary valve replacement, and they may be particularly impacted by new transcatheter therapies. This study provides baseline comparative data for current surgical options that should help inform medical decision making as longer term data become available for transcatheter pulmonary valve replacement and other new technologies.

Catheter-based intracoronary myocardial adenoviral gene delivery: Importance of intraluminal seal and infusion flow rate

Although percutaneous, adenoviral-mediated intracoronary gene delivery to the heart has been demonstrated in some species, consistent and safe methodology is needed before clinical applicability is possible. In this study, we examine the effects of altering intracoronary flow rate and obtaining an adequate seal between the catheter and the coronary lumen on successful cardiac gene delivery and myocardial injury in both piglets and adult rabbits. To study the efficacy of in vivo myocardial gene transfer, we utilized adenoviral vectors containing either the beta(2)-adrenergic receptor or beta-galactosidase. The left circumflex coronary artery of piglets and the right coronary artery of rabbits were catheterized under fluoroscopic guidance and adenovirus solutions were injected using varying flow rates with or without balloon inflation. Successful transgene delivery to the heart was determined approximately 1 week after coronary infusions. Histologic analysis was also performed in all animals to determine the extent of myocardial injury. Our results indicate that efficient and reproducible cardiac transgene expression utilizing intracoronary delivery is dependent upon the infusion flow rate and, in larger animals, requires an intraluminal seal. Excessive flow rate is associated with greater myocardial injury. Thus, conditions can be established and controlled to improve future investigational and clinical application of catheter-based intracoronary myocardial gene therapy.

Younger age and valve oversizing are predictors of structural valve deterioration after pulmonary valve replacement in patients with tetralogy of Fallot

OBJECTIVE We sought to identify predictors of structural valve deterioration after pulmonary valve replacement in patients with tetralogy of Fallot. METHODS A retrospective review of 227 patients with tetralogy of Fallot who underwent stented bioprosthetic pulmonary valve replacement at Childrens Hospital Boston between 1994 and 2009 was performed. Patient and valve characteristics were assessed as potential predictors of structural valve deterioration by using univariate and multivariable analysis. Freedom from pulmonary valve reintervention and structural valve deterioration were determined by using Kaplan-Meier analysis. RESULTS Two hundred twenty-nine pulmonary valve replacement operations were performed, with no early mortalities. Freedom from reintervention and structural valve deterioration were 94% (95% confidence interval, 87%-100%) and 74% (95% confidence interval, 63%-85%) at 5 years, respectively, and median time to reintervention was 6.4 years (range, 2-10.1 years). Younger age and higher indexed valve internal diameter were predictors of reduced time to structural valve deterioration. Among patients aged less than 20 years at the time of pulmonary valve replacement, indexed valve internal diameter was a significant predictor of increased risk of structural valve deterioration. Valve manufacturer was not a significant predictor of structural valve deterioration. CONCLUSIONS Younger age at the time of pulmonary valve replacement and valve oversizing in patients less than 20 years of age at the time of pulmonary valve replacement were significant predictors of structural valve deterioration and could potentially affect the timing of pulmonary valve replacement and the extent of valve oversizing in small children. No statistically significant difference in valve performance was seen between bioprosthetic valve types at short-term follow-up.

Modification of a Stented Bovine Jugular Vein Conduit (Melody Valve) for Surgical Mitral Valve Replacement

We report the use of a Melody valve as a surgical implant in the mitral position in 2 infants, one with severe mitral regurgitation and another with mitral stenosis, where other prostheses are not small enough to be implanted in the mitral position nor expandable as the child grows.