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Intracranial hemorrhage (ICH) can be a devastating complication of extracorporeal life support (ECLS); however, studies on the timing of ICH detection by head ultrasound (HUS) are from 2 decades ago, suggesting ICH is diagnosed by day 5 of ECLS. Given advancements in imaging and critical care, our aim was to evaluate if the timing of ICH diagnosis in infants on ECLS support has changed. Patients6 months old undergoing ECLS 2011-2020 at a tertiary care children's hospital were included. Primary outcome was timing of ICH diagnosis on HUS. Seventy-four infants underwent ECLS for cardiac (54%) or pulmonary (46%) indications. Venoarterial ECLS was most common (88%). Median ECLS duration was 6 days (range 1-26). Sixteen patients were diagnosed with ICH (21.6%), at a median of 2 days postcannulation (range 1-4). Nearly all were4 weeks old at cannulation (93.8%). In conclusion, one-fifth of infants developed ICH diagnosed by HUS while on ECLS, all within the first 4 days of ECLS, consistent with previous literature. Despite advances in critical care and imaging technology, the temporality of ICH diagnosis in infants on ECLS is unchanged.

Background:Although rare, coronary artery anomalies can have significant clinical implications. Total anomalous origin of the coronary arteries from the pulmonary artery (TCAPA) represents a rare subtype of coronary artery anomaly for which little is known. The aim of this review was to characterise the presentation, utilised diagnostic modalities, associated cardiac lesions, and treatment strategies in patients with TCAPA.Methods:A systematic review was performed for cases of TCAPA using PubMed, Embase, and Web of Science. Keywords searched included “total anomalous origin of the coronary arteries from the pulmonary artery,” “single ostium anomalous coronary artery from the pulmonary artery,” and “anomalous origin of both coronary arteries from the pulmonary artery.”Results:Fifty-seven cases of TCAPA were identified in 50 manuscripts. Fifty-eight per cent of patients were male and the median age at presentation was 10 days (mean 1.71 ± 6.6 years, range 0 days–39 years). Most patients were symptomatic at the time of presentation; cyanosis (n = 22) and respiratory distress (n = 14) were the most common symptoms. Cases were most commonly diagnosed at autopsy (n = 26, 45.6%), but operative intervention was pursued in 22 cases (45.6%); aortic re-implantation (n = 14) and a Takeuchi-type repair (n = 7) were the most common routes of repair.Conclusions:The clinical presentation of patients with TCAPA was found to be variable, likely related to the presence of associated cardiac lesions. TCAPA should be considered in patients with suspected anomalous origin of the left coronary artery from the pulmonary artery for the serious consequences that can occur if not promptly corrected.

Q fever is a worldwide zoonosis caused by Coxiella burnetii that can lead to abortion, endocarditis, and death in humans. Researchers utilizing parturient domestic ruminants, including sheep, have an increased risk of occupational exposure. This study evaluated the effectiveness of our screening protocol in eliminating C. burnetii–positive sheep from our facility. From August 2010 to May 2018, all ewes ( N = 306) and select lambs ( N = 272; ovis aries) were screened twice for C. burnetii utilizing a serum Phase I and Phase II antibody immunofluorescence assay (IFA). The first screen was performed by the vendor prior to breeding, and the second screen was performed on arrival to the research facility. Ewes that were positive on arrival screening were quarantined and retested using repeat IFA serology, enzyme-linked immunosorbent assay, buffy coat polymerase chain reaction (PCR), and amniotic fluid PCR. The overall individual seroprevalence of C. burnetii in the flocks tested by the vendor was 14.2%. Ewes with negative Phase I and Phase II IFA results were selected for transport to the research facility. Upon arrival to the facility, two (0.7%) ewes had positive Phase I IFA results. Repeat testing demonstrated seropositivity in one of these two ewes, though amniotic fluid PCR was negative in both. The repeat seropositive ewe was euthanized prior to use in a research protocol. No Q fever was reported among husbandry, laboratory or veterinary staff during the study period. Serologic testing for C. burnetii with IFA prior to transport and following arrival to a research facility limits potential exposure to research staff.

Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.

Anomalous origin of the circumflex or left anterior descending artery from the pulmonary artery (ACxAPA and ALADAPA, respectively) are rare congenital coronary anomalies with clinical presentation varying from an asymptomatic murmur to sudden cardiac arrest. A systematic review was performed, and 46 cases of ACxAPA and 51 cases of ALADAPA were identified in 87 articles. Data were collected and analyzed from each case. A better understanding of ACxAPA/ALADAPA can provide information to providers who encounter this lesion as well as provide insight into coronary artery development which may help in the understanding of coronary artery anomalies.

Q fever is a worldwide zoonosis caused by

We describe an asymptomatic 7-year-old boy who was taken to the operating room for repair of a subaortic membrane and possible Gerbode's defect. He was found to have a double outlet right atrium associated with an accessory atrioventricular valve in addition to a small atrial septal defect and subaortic membrane. Regurgitant flow through this accessory valve led to the left ventricle to right atrial shunt that was seen on preoperative ECHO. The atrial septal defect was repaired and a baffle was used to isolate blood flow across the accessory valve from the left atrium to the left ventricle. The patient was discharged on postoperative day 4 and has been doing well 2 years postoperatively.

The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs ( n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.

Lymphatic abnormalities associated with congenital heart disease are well described, yet the underlying mechanisms remain poorly understood. Using a clinically relevant ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated that lymphatic endothelial cells (LECs) exposed in vivo to chronically increased pulmonary lymph flow accumulate ROS and have decreased bioavailable nitric oxide (NO). Peroxisome proliferator-activated receptor-γ (PPAR-γ), which abrogates production of cellular ROS by NADPH oxidase, is inhibited by Krüppel-like factor 2 (KLF2), a flow-induced transcription factor. We hypothesized that chronically increased pulmonary lymph flow induces a KLF2-mediated decrease in PPAR-γ and an accumulation of cellular ROS, contributing to decreased bioavailable NO in LECs. To better understand the mechanisms that transduce the abnormal mechanical forces associated with chronically increased pulmonary lymph flow, LECs were isolated from the efferent vessel of the caudal mediastinal lymph node of control ( n = 5) and shunt ( n = 5) lambs. KLF2 mRNA and protein were significantly increased in shunt compared with control LECs, and PPAR-γ mRNA and protein were significantly decreased. In control LECs exposed to shear forces in vitro, we found similar alterations to KLF2 and PPAR-γ expression. In shunt LECs, NADPH oxidase subunit expression was increased, and bioavailable NO was significantly lower. Transfection of shunt LECs with KLF2 siRNA normalized PPAR-γ, ROS, and bioavailable NO. Conversely, pharmacological inhibition of PPAR-γ in control LECs increased ROS equivalent to levels in shunt LECs at baseline. Taken together, these data suggest that one mechanism by which NO-mediated lymphatic function is disrupted after chronic exposure to increased pulmonary lymph flow is through altered KLF2-dependent PPAR-γ signaling, resulting in increased NADPH oxidase activity, accumulation of ROS, and decreased bioavailable NO. NEW & NOTEWORTHY Lymphatic endothelial cells, when exposed in vivo to chronically elevated pulmonary lymph flow in a model of congenital heart disease with increased pulmonary blood flow, demonstrate Krüppel-like factor 2-dependent disrupted peroxisome proliferator-activated receptor-γ signaling that results in the accumulation of reactive oxygen species and decreased bioavailable nitric oxide.

Background Anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is a rare congenital cardiac lesion that has been diagnosed in both children and adults with symptoms ranging from an asymptomatic murmur to sudden cardiac death. The aim of this review was to characterize published cases of ARCAPA to better understand this rare congenital coronary anomaly. Methods A systematic review was performed using PubMed, Embase, and Google Scholar for cases of ARCAPA. Keywords searched included: "anomalous origin of the right coronary artery from the pulmonary artery" and "ARCAPA." Results A total of 223 cases of ARCAPA were identified in 193 case reports. There was a slight male predominance (54.5%) and the median age at presentation was 14.0 years. Thirty-eight percent of patients were asymptomatic and most commonly identified during evaluation of a murmur. Angina and dyspnea were the most common presenting symptoms (22.4% and 17.0%, respectively). In symptomatic patients, a bimodal distribution of age at presentation was observed with a peak near birth and another between ages 40 and 60 years. The condition was most commonly diagnosed with coronary angiography (40.4%). Most cases were repaired surgically (72.6%) and reimplantation of the right coronary artery onto the aorta was the most common method of repair (62.3%). Conclusions ARCAPA represents a rare coronary anomaly with great variability in clinical presentation. An understanding of the pathophysiology associated with the lesion is critical when determining treatment strategies.

Background Multimodal pain management strategies are used for analgesia following pectus excavatum repair. However, the optimal regimen has not been identified. We describe our early experience with intercostal cryoablation for pain management in children undergoing the Nuss procedure and compare early cryoablation outcomes to our prior outcomes using thoracic epidural analgesia. Methods A multi-institutional, retrospective review of fifty-two patients undergoing Nuss bar placement with either intercostal cryoablation ( n =26) or thoracic epidural analgesia ( n =26) from March 2013 to January 2016 was conducted. The primary outcome was hospital length of stay. Secondary outcomes included telemetry unit monitoring time, total intravenous narcotic use, duration of intravenous narcotic use, and postoperative complications. Results Patients who underwent intercostal cryoablation had a significant reduction in the mean hospital length of stay, time in a monitored telemetry bed, total use of intravenous narcotics, and the duration of intravenous narcotic administration when compared to thoracic epidural patients. Cryoablation patients had a slightly higher rate of postoperative complications. Conclusion Intercostal cryoablation is a promising technique for postoperative pain management in children undergoing repair of pectus excavatum. This therapy results in reduced time to hospital discharge, decreased intravenous narcotic utilization, and has eliminated epidurals from our practice. Level of evidence Retrospective study – level III.

Associated abnormalities of the lymphatic circulation are well described in congenital heart disease. However, their mechanisms remain poorly elucidated. Using a clinically relevant ovine model of a congenital cardiac defect with chronically increased pulmonary blood flow (shunt), we previously demonstrated that exposure to chronically elevated pulmonary lymph flow is associated with: 1) decreased bioavailable nitric oxide (NO) in pulmonary lymph; and 2) attenuated endothelium-dependent relaxation of thoracic duct rings, suggesting disrupted lymphatic endothelial NO signaling in shunt lambs. To further elucidate the mechanisms responsible for this altered NO signaling, primary lymphatic endothelial cells (LECs) were isolated from the efferent lymphatic of the caudal mediastinal node in 4-wk-old control and shunt lambs. We found that shunt LECs ( n = 3) had decreased bioavailable NO and decreased endothelial nitric oxide synthase (eNOS) mRNA and protein expression compared with control LECs ( n = 3). eNOS activity was also low in shunt LECs, but, interestingly, inducible nitric oxide synthase (iNOS) expression and activity were increased in shunt LECs, as were total cellular nitration, including eNOS-specific nitration, and accumulation of reactive oxygen species (ROS). Pharmacological inhibition of iNOS reduced ROS in shunt LECs to levels measured in control LECs. These data support the conclusion that NOS signaling is disrupted in the lymphatic endothelium of lambs exposed to chronically increased pulmonary blood and lymph flow and may contribute to decreased pulmonary lymphatic bioavailable NO.

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, and to a greater extent shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for pulmonary hypertension associated with CHD.

A Down syndrome female born at 35 wk estimated gestational age with non-immune hydrops fetalis associated with a complete atrioventricular septal defect and large patent ductus arteriosus with hypoxemia, severe anasarca and hypotension was treated successfully with extracorporeal life support for severe cardiopulmonary failure leading to eventual hospital discharge and elective repair of her cardiac defect. The case demonstrates that extracorporeal life support may be an effective therapy when initiated early in patients with non-immune hydrops fetalis associated with significant cardiac abnormalities.

Aim: To compare outcomes of continuous subcutaneous infusion of local anesthetic and epidural analgesia following the Nuss procedure. Patients & methods: A retrospective chart review compared patients managed with subcutaneous local anesthetic infusion (n = 12) versus thoracic epidural (n = 19) following the Nuss procedure from March 2013 to June 2015. Results: There was no difference in hospital length of stay or days on intravenous narcotics. Epidural catheter placement prolonged operating room time (146.58 ± 28.30 vs 121.42 ± 21.98 min, p = 0.01). Average pain scores were slightly higher in the subcutaneous infusion group (3.72 ± 1.62 vs 2.35 ± 0.95, p = 0.02), but of negligible clinical significance. Conclusion: Continuous subcutaneous infusion of local anesthetic could eliminate the need for thoracic epidural for pain management after the Nuss procedure.

In our model of a congenital heart defect (CHD) with increased pulmonary blood flow (PBF; shunt), we have recently shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction and decreased endothelial nitric oxide synthase (eNOS)/heat shock protein (Hsp)90 interactions that contribute to eNOS uncoupling, increased superoxide levels, and decreased bioavailable nitric oxide (NO). Therefore, we undertook this study to test the hypothesis that L-carnitine therapy would maintain mitochondrial function and NO signaling.Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft. Immediately after delivery, lambs received daily treatment with oral L-carnitine or its vehicle.L-Carnitine-treated lambs had decreased levels of acylcarnitine and a reduced acylcarnitine:free carnitine ratio as compared with vehicle-treated shunt lambs. These changes correlated with increased carnitine acetyl transferase (CrAT) protein and enzyme activity and decreased levels of nitrated CrAT. The lactate:pyruvate ratio was also decreased in L-carnitine-treated lambs. Hsp70 protein levels were significantly decreased, and this correlated with increases in eNOS/Hsp90 interactions, NOS activity, and NOx levels, and a significant decrease in eNOS-derived superoxide. Furthermore, acetylcholine significantly decreased left pulmonary vascular resistance only in L-carnitine-treated lambs.L-Carnitine therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation.

There are many variations of sternal anatomy and development. Most of these do not alter chest physiology significantly and as such are not clinically important. Those that do often require surgical treatment early in life. In this chapter, we will review normal sternal development, congenital sternal anomalies and their treatment, and acquired sternal anomalies. Many of the congenital anomalies are often associated with other conditions that result in alterations in the development of other midline structures or thoracic organs.

Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect.An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG- and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.

Primary pleural rhabdomyosarcoma is an extremely rare intrathoracic malignancy. We present a case of a previously healthy 2-year-old male complaining of cough and shortness of breath. The plain film, CT and MRI descriptions of this pleural tumor are presented. This is a fast growing tumor that is indistinguishable radiographically from other large intrathoracic tumors such as pleuropulmonary blastoma.

© 2016 the American Physiological Society.Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.

Background Papillary muscle rupture in the fetus and neonate is a rare event that leads to severe mitral or tricuspid insufficiency and is associated with high perinatal mortality. We undertook surgical repair of this lesion in the neonatal period and report on our midterm results. Methods Three neonates with tricuspid insufficiency and 1 infant with mitral insufficiency, all due to papillary muscle or chordal rupture, underwent surgical repair with artificial chordal replacement and a modification of the de Vega annuloplasty technique that allowed external adjustment of the annulus size under transesophageal echocardiographic guidance after separation from cardiopulmonary bypass. Results All patients recovered well from the operation. There have been no late deaths and no valve-related complications. On discharge, all 3 patients had evidence of trace to mild atrioventricular valve regurgitation. At a median follow-up of 33 months (range, 7 to 50; 123 patient-months), all 4 patients are growing normally. Three patients have had no change in the degree of tricuspid or mitral regurgitation. One patient required reoperation at 54 months postoperatively for acute mitral insufficiency secondary to separation of an artificial chorda from the ventricular wall. Conclusions Surgical repair of critical neonatal tricuspid and mitral insufficiency associated with papillary muscle or chordal rupture is feasible and can result in good early and midterm results. Our modification of the De Vega annuloplasty technique with the ability to externally adjust the size of the annulus under echocardiographic guidance may improve the accuracy of the repair in the neonate.

Background A coronary artery arising from the wrong aortic sinus, with or without a proximal course between the aorta and the pulmonary artery, may predispose to myocardial ischemia, myocardial infarction, or sudden death. Methods We repaired this lesion in 5 symptomatic patients, all of whom had experienced exercise-related chest pain, dyspnea, or syncopal episodes. All patients underwent patch angioplasty of the proximal anomalous coronary artery with glutaraldehyde-treated autologous pericardium. When the coronary artery coursed between the aorta and the main pulmonary artery, the main pulmonary artery was translocated toward the left pulmonary artery to create additional space and prevent compression. Results All patients recovered well and to date have demonstrated no evidence of recurrent myocardial ischemia. Conclusions The combination of coronary artery angioplasty and translocation of the pulmonary artery seems to effectively address all the mechanisms that can generate ischemia.

© 2015 the American Physiological Society. We recently reported superior right ventricle (RV) performance in response to acute afterload challenge in lambs with a model of congenital heart disease with chronic left-to-right cardiac shunts. Compared with control animals, shunt lambs demonstrated increased contractility because of an enhanced Anrep effect (the slow increase in contractility following myocyte stretch). This advantageous physiological response may reflect preservation of a fetal phenotype, since the RV of shunt lambs remains exposed to increased pressure postnatally. Nitric oxide (NO) production by NO synthase (NOS) is activated by myocyte stretch and is a necessary intermediary of the Anrep response. The purpose of this study was to test the hypothesis that NO signaling is increased in the RV of fetal lambs compared with controls and shunt lambs have persistence of this fetal pattern. An 8-mm graft was placed between the pulmonary artery and aorta in fetal lambs (shunt). NOS isoform expression, activity, and association with activating cofactors were determined in fetal tissue obtained during late-gestation and in 4-wk-old juvenile shunt and control lambs. We demonstrated increased RNA and protein expression of NOS isoforms and increased total NOS activity in the RV of both shunt and fetal lambs compared with control. We also found increased NOS activation and association with cofactors in shunt and fetal RV compared with control. These data demonstrate preserved fetal NOS phenotype and NO signaling in shunt RV, which may partially explain the mechanism underlying the adaptive response to increased afterload seen in the RV of shunt lambs.

The objective of this prospective, observational study with consecutive sampling was to assess the reliability, bias, and precision of Nellcor N-395 (N) and Masimo SET Radical (M) pulse oximeters in children with cyanotic congenital heart disease and children with congenital heart disease recovering from cardiopulmonary bypass-assisted surgery admitted to a cardiovascular operating suite and pediatric intensive care unit at a tertiary care community hospital. Forty-six children with congenital heart disease were studied in 1 of 2 groups: (1) those recovering from cardiopulmonary bypass with a serum lactic acid > 2 mmol/L, and (2) those with co-oximetry measured saturations (SaO 2) < 90% and no evidence of shock. Measurements of SaO 2 of whole blood were compared to simultaneous pulse oximetry saturations (SpO 2). Data were analyzed to detect significant differences in SpO 2 readout failures between oximeters and average SpO 2 - SaO 2 ± 1 SD for each oximeter. A total of 122 SaO 2 measurements were recorded; the median SaO 2 was 83% (57 - 100%). SpO 2 failures after cardiopulmonary bypass were 41% (25/61) for N versus 10% (6/61) for M ( P < .001). There was a significant difference in bias (ie, average SpO 2 - SaO 2) and precision (± 1 SD) between oximeters (N, 1.1 ± 3.3 vs M, -0.2 ± 4.1; P < .001) in the postcardiopulmonary bypass group but no significant difference in bias and precision between oximeters in the cyanotic congenital heart disease group (N, 2.9 ± 4.6 vs M, 2.8 ± 6.2; P = .848). The Nellcor N-395 pulse oximeter failed more often immediately after cardiopulmonary bypass than did the Masimo SET Radical pulse oximeter. SpO2 measured with both oximeters overestimated SaO2 in the presence of persistent hypoxemia.

Background Polytetrafluoroethylene (PTFE) and porcine small intestinal submucosa (pSIS) are patch materials used in congenital heart surgery. Porcine SIS is an extracellular-matrix scaffold that may interact with stem or progenitor cells. To evaluate this, we determined the in vitro effects of pSIS and PTFE on human bone marrow mesenchymal stromal cells (MSCs) and cardiac progenitor cells (CPCs) in 3 areas; cell proliferation, angiogenic growth-factor production, and differentiation. Methods Human MSCs and CPCs were seeded onto pSIS and PTFE patches. Cell-seeded patches were cultured and then assessed for cell viability and proliferation and supernatant vascular endothelial growth factor A (VEGFA) levels. Cell proliferation was quantified by MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). Quantitative real-time polymerase chain reaction was performed on cell-seeded scaffolds to determine relative changes in gene expression related to angiogenesis and cardiogenesis. Results The MSCs and CPCs were able to attach and proliferate on pSIS and PTFE. The proliferation rate of each cell type was similar on pSIS. Total RNA isolation was only possible from the cell-seeded pSIS patches. The MSC VEGFA production was increased by pSIS. Porcine SIS promoted an angiogenic gene profile in MSCs and an early cardiogenic profile in CPCs. Conclusions Both PTFE and pSIS allow for varying degrees of cell proliferation. Porcine SIS elicits different phenotypical responses in MSCs as compared with CPCs, which indicates that pSIS may be a bioactive scaffold that modulates stem cell activation and proliferation. These findings highlight the differences in scaffold material strategies and suggest potential advantages of bioactive approaches.

Background/Purpose: Hospital mortality rate among children with hypoplastic left heart syndrome (HLHS) after cardiac repair is well documented, but comparable data after noncardiac, surgical procedures are unknown. The authors hypothesized an increasing number of noncardiac procedures were being performed on children with HLHS, less than 2 years of age, from 1988 to 1997, and that these procedures were associated with a substantial mortality rate. Methods: A retrospective review of hospital discharge data for 2,457 children less than 2 years of age with HLHS for 1988 through 1997 was performed. The authors examined the outcomes of HLHS children undergoing only noncardiac surgical procedures during their hospital stay. Differences in hospital mortality rates between 1988 through 1992 versus 1993 through 1997 were assessed using the X 2 square statistic. Results: Nineteen percent of the 147 children with HLHS undergoing noncardiac, surgical procedures died (95% CI, 13% to 25%). Comparing the 2 study periods, there was no significant change in outcome among HLHS children undergoing noncardiac, surgical procedures (78% v. 83%; P >.1). There was no significant difference in the percentage of hospital discharges with noncardiac, surgical procedures performed per year. Conclusions: Although children with HLHS were not undergoing an increase in the number of noncardiac surgical procedures performed annually, even minor surgical procedures were associated with considerable mortality. Outcomes after noncardiac surgery in high-risk children with congenital heart disease warrant further investigation. J Pediatr Surg 37:1399-1403. Copyright 2002, Elsevier Science (USA). All rights reserved.

Tenascin-C (TN-C) expression and matrix metalloproteinase (MMP) activity are induced within remodeling pulmonary arteries (PAs), where they promote cell growth. Because pulmonary vascular disease in children with congenital heart defects is commonly associated with changes in pulmonary hemodynamics, we hypothesized that changes in pulmonary blood flow regulate TN-C and MMPs. To test this, we ligated the left PAs of neonatal pigs. After 12 wk, we evaluated the levels of TN-C and MMPs in control and ligated lung tissue. Modifying pulmonary hemodynamics increased TN-C mRNA and protein expression, MMP activity, and the DNA-binding activity of Egr-1, a transcription factor that has been shown to activate TN-C expression. To link MMP-mediated remodeling of the extracellular matrix to increased TN-C expression and Egr-1 activity, porcine PA smooth muscle cells were cultivated either on denatured type I collagen, which supported TN-C expression and Egr-1 activity, or on native collagen, which had the opposite effect. These data provide a framework for understanding how changes in pulmonary blood flow in the neonate modify the tissue microenvironment and cell behavior.

Objectives Cardiothoracic surgeons and practitioners of cardiovascular medicine have a long history of humanitarian aid. Although this is worthwhile at multiple levels and occasionally described in some detail, few efforts have a proven algorithm with demonstrable outcomes that suggest effective educational methodology or clinical results approaching accepted standards in developed countries.© 2014 The American Association for Thoracic Surgery Methods Our report provides a stepwise approach to developing highly successful self-sustainable, replicable, and scalable humanitarian congenital cardiac surgical programs, and provides data to allow insight into the efficacy of our model.Results This program model has evolved over 25 years, during which it has been replicated several times and scaled throughout a vast and populous country. Since 1989, Russia has undergone considerable social, political, and economic changes. Our program model proved successful throughout this time despite dynamic social, political, and medical landscapes.Conclusions The positive results of our program model indicate that these methodologies may be helpful to others attempting to address the worldwide shortage of cardiovascular care and particularly the complex interventions required in the management of congenital cardiovascular disease.

Background— The prevalence of Down syndrome (DS)–affected births has increased during the past 30 years; moreover, children with DS have a higher incidence of congenital heart disease compared with their peers. Whether children with DS have better or worse outcomes after repair of congenital heart disease is unclear. We sought to identify differences in in-hospital mortality after cardiac surgery in pediatric patients with and without DS using a large national database. Methods and Results— Children aged P P P P Conclusions— In this large national study, children with DS who underwent repair of congenital heart disease were more likely to survive to discharge than children without DS. Future work is needed to better understand the factors underlying these differences.

Patients with pulmonary hypertension associated with congenital heart disease survive longer with preserved right ventricular (RV) function compared with those with primary pulmonary hypertension. The purpose of this study was to test the hypothesis that superior RV performance can be demonstrated, at baseline and when challenged with increased RV afterload, in lambs with chronic left-to-right cardiac shunts compared with control lambs. A shunt was placed between the pulmonary artery and the aorta in fetal lambs (shunt). RV pressure-volume loops were obtained 4 wk after delivery in shunt and control lambs, before and after increased afterload was applied using pulmonary artery banding (PAB). Baseline stroke volume (8.7 ± 1.8 vs. 15.8 ± 2.7 ml, P = 0.04) and cardiac index (73.0 ± 4.0 vs. 159.2 ± 25.1 ml·min−1·kg−1, P = 0.02) were greater in shunts. After PAB, there was no difference in the change in cardiac index (relative to baseline) between groups; however, heart rate (HR) was greater in controls (168 ± 7.3 vs. 138 ± 6.6 beats/min, P = 0.01), and end-systolic elastance (Ees) was greater in shunts (2.63 vs. 1.31 × baseline, P = 0.02). Control lambs showed decreased mechanical efficiency (71% baseline) compared with shunts. With acute afterload challenge, both controls and shunts maintained cardiac output; however, this was via maladaptive responses in controls, while shunts maintained mechanical efficiency and increased contractility via a proposed enhanced Anrep effect—the second, slow inotropic response in the biphasic ventricular response to increased afterload, a novel finding in the RV. The mechanisms related to these physiological differences may have important therapeutic implications.

We have previously shown decreased pulmonary lymph flow in our lamb model of chronically increased pulmonary blood flow, created by the in utero placement of an 8-mm aortopulmonary shunt. The purpose of this study was to test the hypothesis that abnormal lymphatic function in shunt lambs is due to impaired lymphatic endothelial nitric oxide (NO)-cGMP signaling resulting in increased lymphatic vascular constriction and/or impaired relaxation. Thoracic duct rings were isolated from 4-wk-old shunt ( n = 7) and normal ( n = 7) lambs to determine length-tension properties, vascular reactivity, and endothelial NO synthase protein. At baseline, shunt thoracic duct rings had 2.6-fold higher peak to peak tension and a 2-fold increase in the strength of contractions compared with normal rings ( P < 0.05). In response to norepinephrine, shunt thoracic duct rings had a 2.4-fold increase in vascular tone compared with normal rings ( P < 0.05) and impaired relaxation in response to the endothelium-dependent dilator acetylcholine (63% vs. 13%, P < 0.05). In vivo, inhaled NO (40 ppm) increased pulmonary lymph flow (normalized for resistance) ∼1.5-fold in both normal and shunt lambs ( P < 0.05). Inhaled NO exposure increased bioavailable NO [nitrite/nitrate (NO x); ∼2.5-fold in normal lambs and ∼3.4-fold in shunt lambs] and cGMP (∼2.5-fold in both) in the pulmonary lymph effluent ( P < 0.05). Chronic exposure to increased pulmonary blood flow is associated with pulmonary lymphatic endothelial injury that disrupts NO-cGMP signaling, leading to increased resting vasoconstriction, increased maximal strength of contraction, and impaired endothelium-dependent relaxation. Inhaled NO increases pulmonary lymph NO x and cGMP levels and pulmonary lymph flow in normal and shunt lambs. Therapies that augment NO-cGMP signaling within the lymphatic system may provide benefits, warranting further study.

ObjectiveTo investigate the impact of probiotic Bifidobacterium longum ssp. infantis on the fecal microbiota and plasma cytokines in neonates with congenital heart disease.Study designSixteen infants with congenital heart disease were randomly assigned to receive either B. infantis (4.2 × 10(9) colony-forming units two times daily) or placebo for 8 weeks. Stool specimens from enrolled infants and from six term infants without heart disease were analyzed for microbial composition. Plasma cytokines were analyzed weekly in the infants with heart disease.ResultsHealthy control infants had increased total bacteria, total Bacteroidetes and total bifidobacteria compared to the infants with heart disease, but there were no significant differences between the placebo and probiotic groups. Plasma interleukin (IL)10, interferon (IFN)γ and IL1β levels were transiently higher in the probiotic group.ConclusionCongenital heart disease in infants is associated with dysbiosis. Probiotic B. infantis did not significantly alter the fecal microbiota. Alterations in plasma cytokines were found to be inconsistent.

OBJECTIVES: Surgical reconstructions or palliations of congenital heart defects often require the utilization of patches, of which the ideal material has yet to be discovered. Recently, porcine small intestinal submucosa extracellular matrix (SIS-ECM) has been advocated as an alternative to conventional synthetic or biological patch material. Here, we present our initial experience with SIS-ECM in paediatric cardiovascular reconstructions. METHODS: A retrospective review of all patients

A 13-year obese female with suspected viral myocarditis presented with acute decompensated heart failure. Due to her body habitus, she was a poor candidate for immediate heart transplantation. A peripherally inserted left ventricular assist device (LVAD) was implanted via the right axillary artery. Following device insertion the patient experienced rapid improvement in symptoms. The LVAD provided effective left ventricular unloading for 50 days, promoting myocardial recovery and maintaining excellent patient performance status. The device placement strategy allowed for a high level of activity including completion of school-work and participation in a weight loss program. The patient achieved a 28-pound weight loss, thus improving candidacy for transplantation. Removal of the device was well tolerated and post-removal echocardiography revealed an improvement in the left ventricular ejection fraction (LVEF) from 21% at baseline to 38% after device removal. This case represents a successful application of a peripherally inserted LVAD as a bridge to transplant in a pediatric patient with severe heart failure due to suspected viral myocarditis. For select patients with this condition, a transaxillary LVAD should be considered as a therapeutic option as it is well tolerated and provides effective left ventricle unloading to promote myocardial recovery and maintain performance status.

ObjectiveCarnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.Methods and resultssiRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.ConclusionOur study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.

An infant boy was born at 40 weeks and 3 days of gestation with prenatal diagnoses of a congenital cystic adenomatoid malformation and left ventricular hypoplasia. Preoperative angiography showed right aortic arch, large right-sided patent ductus arteriosus (PDA), left pulmonary artery discontinuous from the main pulmonary artery, left PDA, and a collateral artery from the descending thoracic aorta to the left lower lung (Fig 1; arrow indicates left lung collateral artery). The patient was taken to the operating room for aortic arch reconstruction, unifocalization of the left pulmonary artery, and bilateral PDA ligation. Upon inspection there was a right aortic arch with discontinuous left pulmonary artery originating from the

Diagnosis and treatment of Candida albicans endocarditis can be difficult. We report a case of this rare condition in which a patient on oral fluconazole presented with septic pulmonary emboli without initial echocardiographic evidence of vegetation. Rapid attainment of a tissue diagnosis, along with combined medical surgical treatment proved to be effective for this patient.

We present a case report of a patient with conal septal hypoplasia (supracristal) ventricular septal defect (VSD) complicated by aortic insufficiency (AI) and subpulmonic stenosis from a fibrous membrane. The development of AI with VSD is a well-recognized problem. However, the association of VSD, AI, and significant right ventricular outflow tract obstruction (RVOTO) is less common. Mechanisms of RVOTO include prolapse of an aortic valve cusp across the VSD, as well as infundibular hypertrophy or muscle bundles. Technical echocardiographic issues can make the diagnosis of VSD, AI, and RVOTO challenging. The presence of a discrete fibrous subpulmonary membrane is uncommon in this setting. (J Am Soc Echocardiogr 2000;13:58-60.)

Coronary sinus thrombosis is an extremely rare clinical syndrome with a high fatality rate. It is associated with procedures in the right heart, including insertion of pacemaker wires, Swan-Ganz catheters, and central venous lines. Recognition is often late, and treatment options are not well characterized. We present a case of acute coronary sinus thrombosis and occlusion associated with electrophysiologic ablation for supraventricular tachycardia in an 11-year-old boy. He developed chest pain, ST elevation, a large pericardial effusion, and cardiogenic shock. Emergent cardiac catheterization and percutaneous intervention with rheolytic aspiration thrombectomy resulted in a dramatic recovery. With the advent of new technologies and procedures involving the right heart and coronary sinus, an appreciation of this potentially lethal complication and possible treatment strategies is important.

RISK OF INFECTION, AND ANTIBIOTIC PROPHYLAXIS, are topics that have been debated for decades by those involved in the care of children undergoing cardiac surgery. In this review we attempt to analyse what is known and what has been postulated about this subject. Suggestions regarding the best strategies for treatment have been formulated, based on published reports, as well as current practices worldwide.

Abiotrophia defectiva, one of several nutritionally variant Streptococcus species, is an uncommon but important cause of endocarditis in children. We describe an unusual case complicated by extensive aortitis with pits in the ascending aorta and the proximal aortic arch.