Vascular endothelial growth factor A is associated with the subsequent development of moderate or severe cardiac allograft vasculopathy in pediatric heart transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the leading cause of chronic allograft loss after pediatric heart transplantation. We hypothesized that biomarkers of endothelial injury and repair would predict CAV development in pediatric heart transplant recipients. METHODS: Blood was collected from pediatric heart transplant recipients at the time of routine annual coronary angiography, and the concentrations of 13 angiogenesis-related molecules were determined. The primary end point was the presence of moderate or severe CAV by angiography during a 5-year follow-up period. RESULTS: The study enrolled 48 recipients (57% male) with a median age of 15.5 years (range, 2-22 years) and median time post-transplant of 5.8 years (range, 2-15 years). Eight recipients developed moderate/severe CAV at a median follow-up of 4.7 years, of whom 3 died, 3 underwent retransplantation, 1 had a myocardial infarction, and 1 was listed for retransplantation. Clinical characteristics associated with the development of moderate/severe CAV included prednisone use at enrollment (p = 0.03) and positive recipient cytomegalovirus immunoglobulin G at the time of transplant (p = < 0.01). Multivariable Cox proportional hazards regression identified plasma vascular endothelial growth factor (VEGF)-A concentration greater than 90 pg/ml at the time of blood draw as a significant predictor of time to moderate or severe CAV (hazard ratio, 14.3; 95% confidence interval, 1.3-163). Receiver operating characteristic curve analysis demonstrated that VEGF-A shows moderate performance for association with the subsequent development of CAV (area under the curve, 0.77; 95% confidence interval, 0.61-0.92). CONCLUSIONS: VEGF-A levels in pediatric heart transplant recipients are associated with clinically important CAV progression within the subsequent 5 years.

Risk factors for profuse systemic-to-pulmonary artery collateral burden in hypoplastic left heart syndrome.

Risk factors for developing systemic-to-pulmonary artery collaterals (SPCs) in hypoplastic left heart syndrome (HLHS) are unknown. We performed a retrospective case-control study to identify risk factors for developing a profuse SPC burden in HLHS. Angiograms of 439 patients with HLHS (performed <2 years of age) were reviewed using a previously published angiographic grading scale to identify cases (profuse SPC burden, n = 20) and controls (no or minimal SPC burden, n = 35). In univariate analyses, profuse SPC burden was associated with mitral atresia and aortic atresia subtype (MA/AA) (65% vs 14%, p <0.0001), use of a Sano shunt (70% vs 37%, p = 0.03), longer log-transformed durations of intensive care unit stay (p = 0.02), hospital stay (p = 0.002), pleural drainage (p = 0.008) after stage 1 palliation, lower oxygen saturation at discharge after stage 1 palliation (82 ± 4 vs 85 ± 4%, p = 0.03), and a history of severe shunt obstruction (37% vs 11%, p = 0.04). In a multivariate logistic regression model, profuse SPC burden was associated with MA/AA subtype (odds ratio 6.6), Sano shunt type (odds ratio 8.6), and log-transformed duration of hospital stay after stage 1 (odds ratio 7.9, model p <0.0001, area under the curve 0.88). Nonassociated parameters included fetal aortic valve dilation, severe cyanotic episodes, number of days with open sternum or number of additional exploratory thoracotomies after stage 1 palliation, pulmonary vein stenosis, and restrictive atrial septal defect. In conclusion, in the present case-control study of patients with HLHS, the development of a profuse SPC burden was associated with MA/AA subtype, Sano shunt type, and longer duration of hospital stay after stage 1 palliation.

Bare metal stenting for obstructed small diameter homograft conduits in the right ventricular outflow tract.

OBJECTIVE: Our aim was to assess acute hemodynamic changes with stent insertion, outcomes, and factors associated with increased longevity of stented small diameter homograft conduits. BACKGROUND: Right ventricle-to-pulmonary artery (RV-PA) homograft conduits are commonly used to palliate RV outflow tract obstruction. Bare metal stenting (BMS) and transcatheter pulmonary valve implantation have been shown to relieve obstructed larger diameter conduits and may delay surgical conduit reintervention. Less is known about BMS of small conduits. METHODS AND RESULTS: From 1992 to 2009, BMS was performed to relieve obstruction in 106 homograft conduits that were ≤12 mm at implant. The peak RV-PA gradient fell from 54.3 ± 17.4 mm Hg at baseline to 46.1 ± 15.2 mm Hg after balloon dilation alone and to 25.1 ± 11.4 mm Hg with stenting (all P < 0.001). Higher pre-BMS gradient and RV pressure were the only factors associated with higher post-BMS RV-PA gradient (≥30 mm Hg; both P < 0.001). There were no procedural deaths, two patients required surgical removal of embolized stents. At a median follow-up of 1.6 years, 83 conduits were replaced; freedom from conduit reoperation after BMS was 66% ± 5% at 1 year and 28% ± 5% at 3 years. Factors associated with shorter freedom from reoperation included implanted conduit diameter <10 mm (P = 0.009), higher post-stent RV-PA gradient (P = 0.026), and higher post-stent RV pressure (P < 0.01); only post-stent RV pressure remained significant on multivariable analysis (P < 0.001). CONCLUSION: BMS was acutely effective for the treatment of obstructed small diameter homograft conduits, with low morbidity. Prolongation of small diameter homograft conduit longevity with BMS may be useful in the lifetime management of conduit dysfunction in this patient population.

Pulmonary arterial hypertension: what the large pulmonary arteries tell us.

The morphology of the large intrapulmonary arteries (PAs) in pulmonary hypertension (PH) has received limited attention. Dilation, pruning, abrupt tapering, and tortuosity of PAs occur, but whether different patients have distinct PA phenotypes is unknown. Pulmonary arteriograms from 41 pediatric patients with PH were blindly reviewed by four experts who assigned each angiogram one of three designations: straight (S), tortuous (T), or ambiguous (A). Hemodynamic variables and outcomes were compared to the phenotypes. Thirty patients were either T (19) or S (11); 11 were A. The phenotypes were not associated with age. Tortuous patients had higher PA pressure and resistance than the S group and less likely to react to inhaled nitric oxide than S patients (p < 0.05). Clinical outcomes were similar for the three groups. Thus, in PH patients two subtypes of PA morphology can often be discerned, a reflection of variability in PA tortuosity. These morphological subtypes have differing hemodynamic characteristics. The mechanism(s) underlying these differences is unknown, but neither hydrodynamic factors nor duration of PH are fully explanatory. Because PA morphology might reveal information regarding the biology of pathological remodeling, it might prove enlightening to assess the large PA phenotype in future studies of PH.

Aortic wall injury as a complication of neonatal aortic valvuloplasty: incidence and risk factors.

BACKGROUND: Transcatheter balloon aortic valvuloplasty for critical aortic stenosis in neonates is routinely performed without recognized complication. Aortic wall injury has rarely been observed after balloon aortic valvuloplasty, although the incidence of this complication is unstudied. We reviewed single-center data to determine the incidence of aortic injury during balloon aortic valvuloplasty and to identify risk factors. METHODS AND RESULTS: This retrospective study included all patients <2 months of age who underwent balloon aortic valvuloplasty at our institution from 1985 to 2007. We defined aortic wall injury as an intimal flap, dissection, or vessel rupture as diagnosed by angiography, echocardiography, or direct surgical or postmortem inspection. Primary imaging data were reviewed, as were all procedural and pathology reports, to identify cases of aortic wall injury. Patient and procedural variables were analyzed. Of 187 procedures performed, 28 procedures resulted in aortic wall injury (15%). Injury was recognized at the time of the procedure in only 16 cases (57%). Intimal flaps occurred most commonly in the distal ascending aorta (n=13), most often involving the greater curvature. In multivariate analysis, severe ventricular dysfunction at the time of the procedure (odds ratio, 2.8; P=0.02), greater number of balloon dilation attempts per procedure (odds ratio, 1.5; P=0.005), and novice interventional staff (odds ratio, 2.5; P=0.05) were associated with aortic injury. Incidence of injury was not different in the recent era compared with earlier experience. CONCLUSIONS: Aortic wall injury, specifically creation of an intimal flap, is an underrecognized complication of neonatal balloon aortic valvuloplasty, occurring in 15% of cases even in the recent era. Only severe ventricular dysfunction, greater number of balloon dilations, and novice staff were associated with injury. The clinical sequelae of aortic wall injury remain incompletely understood.

Head-to-head comparison of serum fractionation techniques.

Multiple approaches for simplifying the serum proteome have been described. These techniques are generally developed across different laboratories, samples, mass spectrometry platforms, and analysis tools. Hence, comparing the available schemes is impossible from the existing literature because of confounding variables. We describe a head-to-head comparison of several serum fractionation schemes, including N-linked glycopeptide enrichment, cysteinyl-peptide enrichment, magnetic bead separation (C3, C8, and WCX), size fractionation, protein A/G depletion, and immunoaffinity column depletion of abundant serum proteins. Each technique was compared to results obtained from unfractionated human serum. The results show immunoaffinity subtraction is the most effective means for simplifying the serum proteome while maintaining reasonable sample throughput. The reported dataset is publicly available and provides a standard against which emergent technologies can be compared and evaluated for their contribution to serum-based biomarker discovery.

Quality control metrics for LC-MS feature detection tools demonstrated on Saccharomyces cerevisiae proteomic profiles.

Quantitative proteomic profiling using liquid chromatography-mass spectrometry is emerging as an important tool for biomarker discovery, prompting development of algorithms for high-throughput peptide feature detection in complex samples. However, neither annotated standard data sets nor quality control metrics currently exist for assessing the validity of feature detection algorithms. We propose a quality control metric, Mass Deviance, for assessing the accuracy of feature detection tools. Because the Mass Deviance metric is derived from the natural distribution of peptide masses, it is machine- and proteome-independent and enables assessment of feature detection tools in the absence of completely annotated data sets. We validate the use of Mass Deviance with a second, independent metric that is based on isotopic distributions, demonstrating that we can use Mass Deviance to identify aberrant features with high accuracy. We then demonstrate the use of independent metrics in tandem as a robust way to evaluate the performance of peptide feature detection algorithms. This work is done on complex LC-MS profiles of Saccharomyces cerevisiae which present a significant challenge to peptide feature detection algorithms.

Validation and re-evaluation of a discriminant model predicting anatomic suitability for biventricular repair in neonates with aortic stenosis.

OBJECTIVES: The purpose of this study was to validate and re-evaluate our previously reported scoring systems for predicting optimal management in neonates with aortic stenosis (AS). BACKGROUND: In 1991, we reported a multivariate discriminant equation and an ordinal scoring system for predicting which neonates with AS are suitable for biventricular repair and which are better served by single ventricle management. METHODS: Retrospective analysis was performed to: 1) validate our scoring systems in 89 additional neonates with AS and normal mitral valve area, 2) assess the effects of 5% measurement variation on predictive scores, 3) evaluate our cohort with the Congenital Heart Surgeons' Society scoring system, and 4) repeat the discriminant analysis on the basis of all 126 patients. RESULTS: The original scores each predicted outcome accurately in 68 patients (77%). Minor (5%) measurement variation changed the outcome predicted by the discriminant equation in 8 patients (9%) and by the threshold system in 13 patients (15%). The most accurate model for predicting survival with a biventricular circulation among the full cohort is: 10.98 (body surface area) + 0.56 (aortic annulus z-score) + 5.89 (left ventricular to heart long-axis ratio) - 0.79 (grade 2 or 3 endocardial fibroelastosis) - 6.78. With a cutoff of -0.65, outcome was predicted accurately in 90% of patients. CONCLUSIONS: Both of our original scoring systems are less accurate at predicting outcome than in our original analysis. Revised discriminant analysis yielded a model similar to our original equation that was 90% accurate at predicting survival with a biventricular circulation among neonates with AS and a mitral valve area z-score >-2.

Current management of severe congenital mitral stenosis: outcomes of transcatheter and surgical therapy in 108 infants and children.

BACKGROUND: Severe congenital mitral stenosis (MS) is a rare anomaly that is frequently associated with additional left heart obstructions. Anatomic treatments for congenital MS include balloon mitral valvuloplasty (BMVP), surgical mitral valvuloplasty (SMVP), and mitral valve replacement (MVR), although the optimal therapeutic strategy is unclear. METHODS AND RESULTS: Between 1985 and 2003, 108 patients with severe congenital MS underwent BMVP or surgical intervention at a median age of 18 months (range 1 month to 17.9 years). Anatomic subtypes of MS were "typical" congenital MS in 78 patients, supravalvar mitral ring in 46, parachute mitral valve in 28, and double-orifice mitral valve in 11, with multiple types in approximately 50% of patients. Additional left heart anomalies were present in 82 patients (76%). The first MS intervention was BMVP in 64 patients, SMVP in 33, and MVR in 11. BMVP decreased peak and mean MS gradients by a median of 33% and 38%, respectively (P<0.001), but was complicated by significant mitral regurgitation in 28%. Cross-sectional follow-up was obtained at 4.8+/-4.2 years. Overall, Kaplan-Meier survival was 92% at 1 month, 84% at 1 year, and 77% at 5 years, with 69% 5-year survival during the first decade of our experience and 87% since (P=0.09). Initial MVR and younger age were associated with worse survival. Survival free from failure of biventricular repair or mitral valve reintervention was 55% at 1 year among patients who underwent BMVP and 69% among patients who underwent supravalvar mitral ring resection initially. Among patients who underwent BMVP, survival free from failure of biventricular repair or MVR was 79% at 1 month and 55% at 5 years, with worse outcome in younger patients and those who developed significant postdilation mitral regurgitation. CONCLUSIONS: BMVP effectively relieves left ventricular inflow obstruction in most infants and children with severe congenital MS who require intervention. However, surgical resection is preferable in patients with MS due to a supravalvar mitral ring. Five-year survival is relatively poor in patients with severe congenital MS, with worse outcomes in infants and patients undergoing MVR, but has improved in our more recent experience. Many patients have undergone second procedures for either recurrent/residual MS or mitral regurgitation resulting from dilation-related disruption of the mitral valve apparatus.

Use of stents to maintain atrial defects and fontan fenestrations in congenital heart disease.

Maintaining patent atrial septal communications or fenestrations can be vital in conditions requiring adequate decompression of the atria or Fontan baffle. We have recently deployed stents for this purpose, and the aim of this retrospective analysis is to describe our experience. All 26 patients undergoing such stent placement were retrospectively studied and for neonates with hypoplastic left heart syndrome (HLHS) and patients with Fontan fenestrations, their data were compared to controls undergoing transseptal static balloon dilation during the same time period. All 7 stented neonates with HLHS survived to their Norwood procedure and 57% survived to hospital discharge, similar to those who had static balloon dilation. Complications occurred in both HLHS groups but transient complete heart block was only seen in the control group, which also had larger balloons used (10.3 mm vs 7 mm, P=0.002). The success rate for patients undergoing stent placement in Fontan fenestrations was 64% compared to 76% with dilation alone. Complications were seen in 64% of the Fontan stented group compared to 39% for controls. There were 5 other patients with complex lesions (3 of whom were on the Extracorporeal Membrane Oxygenator) in whom stent placement successfully maintained atrial communication patency. Atrial septal stent placement in neonates with HLHS with restrictive defects is effective and appears at least as safe as static balloon dilation. On the other hand, initial fenestration stent placement is indicated only after extracardiac Fontan procedures in which the previous fenestration location cannot be found.

Left heart growth, function, and reintervention after balloon aortic valvuloplasty for neonatal aortic stenosis.

BACKGROUND: Transcatheter balloon aortic valvuloplasty (BAVP) has become the first-line treatment for critical aortic stenosis (AS) in neonates. However, little is known about the growth and function of left heart structures or about patterns of reintervention on the left heart after neonatal BAVP. METHODS AND RESULTS: Between 1985 and 2002, 113 patients underwent neonatal BAVP at < or =60 days of age. There were 16 early deaths (14%), with a significant decrease from 1985 to 1993 (22%) to 1994 to 2002 (4%), and 6 patients had successful early conversion to a univentricular circulation. In the short term, the mean relative gradient reduction was 54+/-26%, and significant aortic regurgitation (AR) developed in 15% of patients. The 91 early survivors with a biventricular circulation were followed up for 6.3+/-5.3 years, during which time there was a steady increase in the frequency of significant AR. Freedom from moderate or severe AR was 65% at 5 years. In almost all patients with a baseline aortic annulus z score less than -1, the annulus diameter increased to within the normal range within 1 to 2 years. Similarly, left ventricular (LV) end-diastolic dimension z scores, which ranged from -5 to 7.5 before BAVP, normalized within 1 to 2 years in nearly all patients with a predilation z score less than -1. Among early survivors with a biventricular circulation, reintervention-free survival on the LV outflow tract was 65% at 1 year and 48% at 5 years, with younger age, higher pre- and post-BAVP gradients, and a larger balloon-annulus diameter ratio associated with decreased reintervention-free survival (P<0.01). Seventeen surgical interventions were performed on the aortic valve in 15 patients, including replacement in 7. Survival free from aortic valve replacement was 84% at 5 years. CONCLUSIONS: BAVP for AS during the first 60 days of life results in short-term relief of AS in the majority of patients. Among early survivors, initially small left heart structures may be associated with worse subacute outcomes but typically normalize within 1 year. Reintervention for residual/recurrent AS or iatrogenic AR is relatively common, particularly during the first year after BAVP, but aortic valve replacement during early childhood is seldom necessary.

Aortico-left ventricular tunnel: 35-year experience.

OBJECTIVES: The purpose of this study was to review our 35 years of experience with aortico-left ventricular tunnel (ALVT), with emphasis on diagnosis, surgical details, and follow-up. BACKGROUND: Aortico-left ventricular tunnel is a rare congenital anomaly. Neonatal surgery has been advocated in all due to long-term concern of valvar aortic regurgitation (AR). METHODS: We identified 11 patients from 1963 to August 2002. Clinical, echocardiographic, catheterization, and surgical details were reviewed. RESULTS: Eight of 11 patients presented at less than six months old (six with congestive heart failure) and three later with a murmur, all with clinical evidence of AR. Associated lesions, most commonly aortic valve and coronary artery anomalies, were present in 45%. Catheter occlusion was considered but not performed in five. Spontaneous occlusion was documented in one. Ten had surgery (nine in our institution), seven with direct suture and two by patch closure of the aortic end of the AVLT. At follow-up (median, 5 years; 1 month to 35 years), all were asymptomatic; three had residual ALVT (one moderate, two small/trivial), with at most mild AR. CONCLUSIONS: Aortico-left ventricular tunnel is a rare cardiac malformation with a good post-operative long-term outcome. Associated lesions occurred in 45%. Catheterization should be reserved for patients with unclear non-invasive findings or transcatheter closure. We recommend surgery for most patients. We report spontaneous closure in one patient, prompting consideration of conservative follow-up in rare small, asymptomatic AVLT.

Management of coronary artery fistulae. Patient selection and results of transcatheter closure.

OBJECTIVES: We report short-term findings in 33 patients after transcatheter closure (TCC) of coronary artery fistulae (CAF) and compare our results with those reported in the recent transcatheter and surgical literature. BACKGROUND: Transcatheter closure of CAF has been advocated as a minimally invasive alternative to surgery. METHODS: We reviewed all patients presenting with significant CAF between January 1988 and August 2000. Those with additional complex cardiac disease requiring surgical management were excluded. RESULTS: Of 39 patients considered for TCC, occlusion devices were placed in 33 patients (85%) at 35 procedures and included coils in 28, umbrella devices in 6 and a Grifka vascular occlusion device in 1. Post-deployment angiograms demonstrated complete occlusion in 19, trace in 11, or small residual flow in 5. Follow-up echocardiograms (median, 2.8 years) in 27 patients showed no flow in 22 or small residual flow in 5. Of the 6 patients without follow-up imaging, immediate post-deployment angiograms showed complete occlusion in 5 or small residual flow in 1. Thus, complete occlusion was accomplished in 27 patients (82%). Early complications included transient ST-T wave changes in 5, transient arrhythmias in 4 and single instances of distal coronary artery spasm, fistula dissection and unretrieved coil embolization. There were no deaths or long-term morbidity. Device placement was not attempted in 6 patients (15%), because of multiple fistula drainage sites in 4, extreme vessel tortuosity in 1 and an intracardiac hemangioma in 1. CONCLUSIONS: A comparison of our results with those in the recent transcatheter and surgical literature shows similar early effectiveness, morbidity and mortality. From data available, TCC of CAF is an acceptable alternative to surgery in most patients.