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Endothelin (ET)-1, a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproET-1, by endothelin-converting enzyme (ECE)-1 activity. ET-1 may bind to two receptors, ETAand ETB, that mediate vasoconstriction and vasodilation in the ovine fetal lung, respectively. ET-1 contributes to high pulmonary vascular resistance in experimental perinatal pulmonary hypertension induced by ligation of the ductus arteriosus in the fetal lamb. Physiological studies in this model have demonstrated enhanced ETA- and diminished ETB-receptor activities and a threefold increase in lung immunoreactive ET-1 protein content. We hypothesized that increased ET production and an imbalance in receptor expression would favor vasoconstriction and smooth muscle cell hypertrophy in pulmonary hypertension and may be partially due to alterations in gene expression. To test this hypothesis, we studied lung mRNA expression of preproET-1, ECE-1, and the ETAand ETBreceptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late-gestation fetuses (135 ± 3 days; 147 days = term) and from animals with pulmonary hypertension after ductus arteriosus ligation for 8 days (134 ± 4 days). Ductus arteriosus ligation increased right ventricular hypertrophy [control 0.56 ± 0.02 vs. hypertension 0.85 ± 0.05; right ventricle/(left ventricle + septum); P < 0.05]. Northern blot analysis was performed using cDNA probes and was normalized to the signal for 18S rRNA. We found a 71 ± 24% increase in steady-state preproET-1 mRNA ( P < 0.05) and a 62 ± 5% decrease in ETBmRNA ( P < 0.05) expression in ductus arteriosus ligation. ECE-1 and ETA-receptor mRNA expression did not change. We conclude that chronic intrauterine pulmonary hypertension after ductus arteriosus ligation increases steady-state preproET-1 mRNA and decreases ETB-receptor mRNA without changing ECE-1 mRNA or ETA-receptor mRNA expression. These findings suggest that increased ET-1 production and decreased ETB-receptor expression may contribute to increased vasoconstrictor tone in this experimental model of neonatal pulmonary hypertension.

Nitric oxide (NO) modulates pulmonary vascular resistance (PVR) in the normal fetus by increasing the cyclic guanosine 3',5'-monophosphate (cGMP) content of pulmonary vascular smooth muscle cells. Although several vasodilator stimuli, including acetylcholine, decrease fetal PVR through the release of endogenous NO, fetal pulmonary vasodilation is often transient despite prolonged treatment. Because cGMP is hydrolyzed and inactivated by cGMP-specific (type 5) phosphodiesterases (PDE5), we hypothesized that PDE5 activity contributes to high fetal PVR and limits the capability of the fetal pulmonary circulation to dilate or sustain vasodilation in response to cGMP-dependent stimuli. To test this hypothesis, we studied the hemodynamic effects of dipyridamole in 19 late-gestation fetal lambs. To determine whether dipyridamole-induced vasodilation is dependent upon basal NO release, we measured the response to dipyridamole before and after pretreatment with the NO synthase antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA completely blocked dipyridamole-induced pulmonary vasodilation. To evaluate the effect of dipyridamole on pulmonary vasodilation due to the stimulated release of NO, we studied effects of prolonged intrapulmonary acetylcholine infusions, with and without concomitant administration of low-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusions, acetylcholine and dipyridamole individually caused transient pulmonary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study period. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of inhaled NO (5 and 20 ppm) alone and in combination with dipyridamole during mechanical ventilation with low FlO2. The combination of dipyridamole with inhaled NO resulted in a greater degree of pulmonary vasodilation than that achieved with inhaled NO alone. We conclude that dipyridamole-induced pulmonary vasodilation is dependent on endogenous (basal) NO production and that dipyridamole potentiates vasodilator responses to endothelium-dependent and -independent dilators in the ovine fetal pulmonary circulation. We speculate that PDES activity opposes vasodilation and maintains high PVR in the normal fetal lung.

Background Although many predictors have been evaluated, a set of strong independent prognostic mortality indicators has not been established in children with pediatric pulmonary arterial hypertension (PAH). The aim of this study was to identify a combination of clinical and molecular predictors of survival in PAH. Methods This single-center, retrospective cohort study was performed from children with PAH between 2001 and 2008 at Children's Hospital Colorado. Blood samples from 83 patients (median age of 8.3 years-old) were obtained. We retrospectively analyzed 46 variables, which included 27 circulating proteins, 7 demographic variables and 12 hemodynamic and echocardiographic variables for establishing the best predictors of mortality. A data mining approach was utilized to evaluate predictor variables and to uncover complex data structures while performing variable selection in high dimensional problems. Results Thirteen children (16%) died during follow-up (median; 3.1 years) and survival rates from time of sample collection at 1 year, 3 years and 5 years were 95%, 85% and 79%, respectively. A subset of potentially informative predictors were identified, the top four are listed here in order of importance: Tissue inhibitors of metalloproteinases-1 (TIMP-1), apolipoprotein-AI, RV/LV diastolic dimension ratio and age at diagnosis. In univariate analysis, TIMP-1 and apolipoprotein-AI had significant association with survival time (hazard ratio [95% confidence interval]: 1.25 [1.03, 1.51] and 0.70 [0.54–0.90], respectively). Patients grouped by TIMP-1 and apolipoprotein-AI values had significantly different survival risks (p

Purpose: In paediatric pulmonary arterial hypertension (PAH), it remains uncertain whether disease progression and prognosis differ between the diagnostic PAH-subclasses. The purpose of this study was to determine whether in the current era patient characteristics, treatment strategies and outcome differ between paediatric idiopathic/hereditary PAH (IPAH/HPAH) patients and paediatric PAH associated with congenital heart disease (PAH-CHD) patients. Methods: Paediatric IPAH/HPAH and PAH-CHD patients seen in three major referral centres between 2000 and 2010 were enrolled in this study according to uniform inclusion criteria: right heart catheterization confirmed PAH, diagnosed after 1997 at age

Although endogenous nitric oxide (NO) modulates basal tone in the fetal pulmonary and systemic circulations, little is known about its role in regulating ductus arteriosus (DA) tone. Immunostaining of DA tissue from late-gestation fetal lambs demonstrated strong staining for endothelial NO synthase (eNOS) in DA endothelium. To study the physiological role of the NO and guanosine 3',5'-cyclic monophosphate (cGMP) system in the DA in vivo, we measured the hemodynamic effects of NG-nitro-L-arginine (L-NNA; 30 mg), a NOS inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and indomethacin (0.8 mg), a cyclooxygenase inhibitor, in 10 chronically prepared late-gestation fetal lambs. L-NNA increased main pulmonary artery (MPA) and aortic pressures (P < 0.05 vs. baseline) but did not change the pressure gradient between the MPA and the aorta. L-NNA caused a small decrease in DA flow and a slight rise in resistance across the DA. Methylene blue increased both MPA pressure and the pressure gradient between the MPA and the aorta from 0.3 +/- 0.2 (baseline) to 7.0 +/- 2.7 mmHg (P < 0.05). Indomethacin increased both MPA pressure and the pressure gradient between the MPA and the aorta from 1.1 +/- 0.4 (baseline) to 6.3 +/- 1.5 mmHg (P < 0.05) after 40 min. Indomethacin decreased DA flow and increased DA resistance. We conclude that eNOS is in fetal DA endothelial cells and that NOS inhibition causes constriction of the DA in vivo. DA constriction after NOS inhibition is minimal, especially in comparison with cyclooxygenase inhibition. Methylene blue also constricts the DA, suggesting that guanylate cyclase activity contributes to DA relaxation. We speculate that, although the NO and cGMP system modulates DA tone, prostaglandins may play a greater role.

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief (10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether endothelium-dependent pulmonary vasodilation is selectively impaired by chronic intrauterine pulmonary hypertension, we compared the hemodynamic effects of an endothelium-dependent agonist, acetylcholine (ACh), with an endothelium-independent agonist, atrial natriuretic peptide (ANP), before, during, and after development of pulmonary hypertension in five late-gestation fetal lambs. Pulmonary hypertension was produced over 9–12 days by progressive inflation of a vascular occluder around the ductus arteriosus. Age-matched fetal lambs (n = 5) without occluders served as controls. Mean pulmonary arterial pressure increased from 44 +/- 2 (baseline) to 65 +/- 4 Torr after 10-12 days of inflation (P < 0.05). Left lung pulmonary vascular resistance (PVR) increased from 0.52 +/- 0.06 to 0.72 +/- 0.11 Torr.ml-1.min over 10 days (P < 0.05). O2 saturation remained at > 40% during the study period. Although brief intrapulmonary infusions of ACh (1.5 micrograms over 15 min) lowered left lung PVR by 29 +/- 8% before ductus arteriosus compression, ACh-induced pulmonary vasodilation was absent after 9–12 days of pulmonary hypertension. In contrast, the vasodilator response to ANP remained intact throughout the study period. ACh- and ANP-induced vasodilation did not change with time in control animals. In five hypertensive animals delivered by cesarean section, inhaled NO (20 ppm) reduced left lung PVR from levels achieved during ventilation with 100% O2 alone (0.61 +/- 0.31 to 0.24 +/- 0.007 Torr.ml-1.min), increased arterial O2 saturation from 51 +/- 14 to 84 +/- 13%, and increased arterial PO2 from 29 +/- 11 to 106 +/- 34 Torr.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the clinical utility of tissue Doppler imaging (TDI) in assessment of disease severity and prognostic value in children with idiopathic pulmonary arterial hypertension (PAH).A prospective study was performed to evaluate TDI velocities (systolic myocardial velocity, early diastolic myocardial relaxation velocity [Em], late diastolic myocardial velocity associated with atrial contraction), brain natriuretic peptide, New York Heart Association (NYHA) functional class, and hemodynamics in 51 children (mean age; 11.6 years) with idiopathic PAH. Fifty-one healthy children with comparable demographics served as controls.Em, Em/late diastolic myocardial velocity associated with atrial contraction ratio, and systolic myocardial velocity at mitral annulus, septum, and tricuspid annulus in PAH were significantly reduced compared with controls. Tricuspid Em had significant inverse correlations with plasma brain natriuretic peptide levels (r = -0.60, P.001), right ventricular end-diastolic pressure (r = -0.79, P.001), and mean pulmonary arterial pressure (r = -0.67, P.001). Statistically significant differences were observed in tricuspid Em between NYHA functional class II vs combined III and IV (mean and SD; 11.9 ± 4.2 cm/s vs 8.2 ± 3.6 cm/s, respectively, P = .002). Cumulative event-free survival rate was significantly lower when tricuspid Em was ≤8 cm/s (log-rank test, P.001)Tricuspid Em velocity correlated with NYHA functional class as disease severity and may serve as a useful prognostic marker in children with idiopathic PAH. The present study is the initial report to evaluate TDI velocities against midterm outcome variables in a relatively large pediatric PAH population.

To determine whether the N-terminal fragment of B-type natriuretic peptide (NTproBNP) was a biomarker of clinical, laboratory, and echocardiographic abnormalities in children with homozygous sickle cell disease.We conducted a single-center retrospective study that consisted of analysis of data from November 2007 to December 2010. We correlated serum NTproBNP with clinical and laboratory findings, echocardiographic data, and New York Heart Association (NYHA) functional class.NTproBNP levels from 42 children (median age, 9 years; 52% female) had significant correlations with hemoglobin (r = -0.63, P.05), and echocardiographic measurements including tricuspid regurgitant velocity (r = 0.46, P.05), lateral E' (r = -0.52, P.05), and lateral E/E' ratio (r = 0.60, P.05), suggesting diastolic dysfunction. In addition, NTproBNP levels increased from NYHA functional class I to class III and had a significant linear correlation with the NYHA functional class (r = 0.69, P.05).NTproBNP correlated with low hemoglobin and tissue Doppler data as indicators of diastolic dysfunction. Elevated NTproBNP may be a prognostic biomarker for the presence of diastolic dysfunction related to anemia in children with sickle cell disease.

We describe a case of variant angina associated with acute myocardial ischemia in an adolescent presenting with severe chest pain and transient ST elevation. Subsequent cardiac catheterization revealed normal coronary anatomy, and the patient has been asymptomatic since discharge on calcium channel blockers. Variant angina is a rare cause of chest pain in adolescents.

The authors discuss the case of a 7-year-old female who presented with exertional cyanosis and was found to have pulmonary arterial hypertension. Despite normal left-sided heart function, the patient developed pulmonary oedema in response to pulmonary vasodilator therapy, increasing suspicion for pathology in the pulmonary capillaries and veins. Lung biopsy confirmed a diagnosis of pulmonary capillary haemangiomatosis (PCH), a rare cause of pulmonary hypertension in both children and adults. The diagnosis requires lung biopsy and is often made postmortem. She was treated with interferon α-2a and doxycycline for their antiangiogenic properties and reports of disease regression. Although she initially demonstrated improvement in her pulmonary hypertension in response to these medications, she succumbed to the disease within the time frame previously reported for PCH.

Patient's with severe Ebstein's anomaly of the tricuspid valve presenting in the newborn period often have profound cyanosis and are at increased risk for sudden death. 1,2 Several strategies have been used to manage these complicated patients. A recent surgical technique described by Starnes et al 3 involved oversewing the tricuspid valve and creating a Blalock-Taussig shunt; this palliation leads to eventual Fontan repair. Further options include Blalock-Taussig shunt alone, cardiac transplantation, extracorporeal membrane oxygenation and tricuspid valve repair or replacement. 1,4,5 In this article, we report 3 consecutive newborns with severe Ebstein's anomaly and cyanosis who were treated with prolonged prostaglandin E 1 infusions. These cases suggest that prostaglandin E 1 may obviate the need for early surgical intervention in critically ill neonates with Ebstein's anomaly and allow survival until surgical management can be pursued at lower risk.

To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy.We conducted a retrospective review of 25 patients2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms.Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis.These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.

Background Pulmonary hypertension has not been described as a predisposing risk factor for high-altitude pulmonary edema (HAPE) in children. Previous studies have shown an association of HAPE with abnormally increased pulmonary vasoreactivity to hypoxia but generally normal pulmonary artery pressure (PAP) after recovery. Objective To describe HAPE of relatively rapid onset and its management in a series of children residing at moderate to high altitudes, all of whom had underlying pulmonary hypertension. Methods and Results From 1997 to 2003, 30 children came to our center with high-altitude illness. Of these, 10 children (aged 4-18 years; male-female ratio, 8:2) living at moderate to high altitudes (1610-3050 m) underwent cardiac catheterization after recovery from HAPE, and all were found to have chronic pulmonary hypertension (mean PAP, 38 ± 9 mm Hg; pulmonary vascular resistance, 8.6 ± 2.8 U × m 2 ). Increases in PAP and pulmonary vascular resistance to hypoxia (16% oxygen) suggest that these children have a reactive pulmonary pressor response and hence are susceptible to HAPE. Six of the 10 patients had predisposing cardiopulmonary abnormalities, and 5 of these 6 patients did not receive a diagnosis prior to the onset of HAPE. Long-term treatment with calcium channel blockers, bosentan, sildenafil citrate, and/or oxygen lowered PAP, improved symptoms, and prevented the recurrence of HAPE. Conclusion Children living at altitude who develop HAPE should undergo screening for diagnosis of underlying cardiopulmonary abnormalities including pulmonary hypertension.

This paper describes a test method for measuring the mechanical properties of small, nonlinear membrane samples from a rat model for pulmonary hypertension. The size and nonlinearity of the pulmonary artery samples poses a challenge for developing a test method that will generate quality, reproducible data in the pressure range experienced by the hypertensive pulmonary artery. The experimental method described here has sufficient precision to yield a combined relative standard uncertainty of 4 %. The method is calibrated against 75 µm thick latex and the data agree well with the neo-Hookian model.

Pulmonary Vascular Effects of Prolonged Estrogen Receptor Blockade on the Response to Birth-Related Stimuli in Fetal Lambs

Exaggerated Pulmonary Vasoconstrictor Response to Acute Hypoxia in the Endothelin B Receptor Deficient Rat

Acute Hemodynamic Effects of Pulsed Delivery of Low Flow Nasal Nitric Oxide in Children with Pulmonary Hypertension † 118

Inducible Nitric Oxide Synthase Inhibitors Increase Pulmonary Vascular Resistance in the Late-Gestation Fetus. • 335

Decreased endothelial nitric oxide synthase (eNOS) may contribute to the high pulmonary vascular resistance (PVR) which characterizes persistent pulmonary hypertension of the newborn (PPHN). In experimental PPHN produced by ductus arteriosus (DA) ligation in fetal lambs, eNOS mRNA, protein, and activity are reduced. Because E2 upregulates eNOS in several experimental settings, we hypothesized that estradiol treatment would attenuate the hemodynamic and histologic changes of pulmonary hypertension (PH), and that this effect may be mediated by upregulation of eNOS. We studied the effects of chronic E2 treatment of late gestation (126-128 d; term=147 d) fetal lambs. Immediately following DA ligation and placement of catheters in the main pulmonary artery (MPA) and aorta, fetal lambs were treated with daily infusion of E2 (10 mcg; n=6) or saline (ctrl; n=5) in the MPA. Eight days after the initial surgery, a left pulmonary artery (LPA) flow transducer was placed and lambs were then delivered and mechanically ventilated with FiO2=1.0. Mean pulmonary artery pressure inutero was not different between groups(73±7 vs. 79±3 mm Hg, day 8; E2 vs. ctrl). At delivery, E2 animals had lower PVR, better oxygenation, and higher LPA flow(table; *=p

The nitric oxide (NO) - cGMP cascade modulates perinatal pulmonary vascular tone. cGMP-specific (type V) phosphodiesterase (PDE5) hydrolyzes cGMP, limiting vasodilation and maintaining high pulmonary vascular resistance (PVR) in the fetus. Two new drugs, E4021 (Eisai) and DMPPO (Glaxo-Welcome), have been developed which cause potent and selective inhibition of PDE5 activity. To test the hypothesis that PDE5 activity contributes to high PVR in the fetal lung, we studied the hemodynamic effects of these novel PDE5 antagonists in 11 chronically-prepared, late gestation fetal lambs (mean gestational age, 132 days; 147 days, term). At surgery, we placed catheters in the main pulmonary artery (PAP), aorta (AoP), left atrium (LAP) and amniotic cavity to measure pressure. A catheter was placed in the left pulmonary artery (LPA) to infuse drug directly into the left lung. An ultrasonic flow transducer was placed on the LPA to measure left lung blood flow. After at least 48 hours recovery from surgery, E4021 (doses: 0.04 - 4 mg) were infused over 10 minutes into the LPA. Hemodynamic measurements were recorded at baseline and at 10 minute intervals for 60 minutes. E4021 caused dose-related pulmonary vasodilation, decreasing PVR from baseline by 30% (0.04 mg) to 58% (4 mg; p 1 mg. Equimolar infusions of DMPPO caused a similar fall in PVR(61%). To determine the importance of endogenous NO in stimulation of cGMP production, E4021 (1 mg) was infused before and after treatment with nitro-L-arginine (L-NA), a selective inhibitor of NO synthase. L-NA completely blocked E4021 -induced pulmonary vasodilation. We conclude that E4021 and DMPPO cause potent pulmonary vasodilation in the ovine fetus. These findings support the hypothesis that PDE5 plays a critical role in regulation of pulmonary vascular tone in the developing lung. We speculate that PDE5 inhibitors may provide a new therapy for pulmonary hypertension.

Endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproendothelin-1 (ppET-1), by ET converting enzyme (ECE-1) activity. In the fetal lung, the effects of ET-1 are also dependent upon stimulation of ET A and B receptors, which mediate vasoconstriction and vasodilation, respectively. Past studies have suggested that ET-1 contributes to high pulmonary vascular resistance (PVR) in an experimental model of perinatal pulmonary hypertension due to chronic ligation of the ductus arteriosus (DA). Physiologic studies in this model have demonstrated altered ET A and ET B activities after DA ligation, but little is known about mechanisms contributing to these changes in ET-1 activity. To further study the role of ET-1 in pulmonary hypertension after DA ligation, we studied lung mRNA expression of ppET-1, ECE-1, and the ET A and ET B receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late gestation fetuses (135±3 days; 147 days = term) and from animals with pulmonary hypertension after DA ligation for 8 days(134±4 days). DA ligation increased right ventricular hypertrophy(0.56±0.02 vs 0.85±0.05, right ventricle / left ventricle + septum, p

LONG TERM ECHOCARDIOGRAPHIC FOLLOW-UP OF INFANTS WITH SEVERE PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN. † 1677

Pulmonary hypertension is characterized by altered pulmonary vascular responsiveness to certain stimuli such as alveolar hypoxia. Although the mechanism of hypoxia-induced pulmonary vasoconstriction is not completely understood, recent evidence suggests that decreased production of endogenous nitric oxide (NO) and cGMP are partly responsible. We hypothesized that increasing pulmonary vascular cGMP concentration by inhibiting cGMP degradation might influence vasoreactivity in patients with heightened pulmonary responsiveness. To test this hypothesis, we studied the effects of dipyridamole (D), a potent cGMP phosphodiesterase (PDE5) inhibitor, in 4 patients with exaggerated hypoxia-induced pulmonary hypertension. Hemodynamic measurements including mean pulmonary, aortic, and pulmonary capillary wedge pressures (PAP, AoP, PCWP; mmHg), cardiac index (CI; liters/ min/M2), and pulmonary and systemic vascular resistances (PVRI and SVRI; indexed units) were recorded sequentially on room air (BL1 and BL2) and during hypoxic exposure (16% O2) before and after administration of D (0.6 mg/kg). D decreased baseline PAP and AoP (35 +/- 3 to 26 +/- 2 and 80 +/- 9 to 67 +/- 10 respectively; p

DIPYRIDAMOLE, A cGMP PHOSPHODIESTERASE INHIBITOR, ATTENUATES REBOUND PULMONARY HYPERTENSION AFTER WITHDRAWAL OF INHALED NITRIC OXIDE IN POSTOPERATIVE CONGENITAL HEART DISEASE. • 163

Las clasificaciones actuales de la hipertensión pulmonar han contribuido significativamente al conocimiento de la enfermedad vascular pulmonar, han facilitado ensayos farmacológicos y han mejorado nuestro conocimiento de las cardiopatías congénitas del adulto; sin embargo estas clasificaciones no son aplicables completamente a la enfermedad en el niño. La clasificación que aquí se propone se basa principalmente en la práctica clínica. Los objetivos específicos de esta nueva clasificación son mejorar las estrategias diagnósticas, promover la investigación clínica, mejorar nuestro conocimiento de la patogénesis, de la fisiología y de la epidemiología de la enfermedad y orientar el desarrollo de modelos de la enfermedad humana en el laboratorio y estudios en animales; también puede servir como un recurso docente. Se hace énfasis en los conceptos de maladaptación perinatal, alteraciones del desarrollo e hipoplasia pulmonar como factores causantes de la hipertensión pulmonar pediátrica; así mismo, en la importancia de los múltiples síndromes malformativos congénitos, genéticos y cromosómicos en la presentación de la hipertensión pulmonar pediátrica. La enfermedad vascular pulmonar hipertensiva en niños se divide en diez grandes categorías.Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients.

ObjectivesWe sought to analyze the indications and outcome of extracorporeal membrane oxygenation (ECMO) for early primary graft failure and determine its impact on long-term graft function and rejection risk.BackgroundEarly post-operative graft failure requiring ECMO can complicate heart transplantation.MethodsA retrospective review of all children requiring ECMO in the early period after transplantation from 1990 to 2007 was undertaken.ResultsTwenty-eight (9%) of 310 children who underwent transplantation for cardiomyopathy (n = 5) or congenital heart disease (n = 23) required ECMO support. The total ischemic time was significantly longer for ECMO-rescued recipients compared with our overall transplantation population (276 ± 86 min vs. 242 ± 70 min, p < 0.01). The indication for transplantation, for ECMO support, and the timing of cannulation had no impact on survival. Hyperacute rejection was uncommon. Fifteen children were successfully weaned off ECMO and discharged alive (54%). Mean duration of ECMO was 2.8 days for survivors (median 3 days) compared with 4.8 days for nonsurvivors (median 5 days). There was 100% 3-year survival in the ECMO survivor group, with 13 patients (46%) currently alive at a mean follow-up of 8.1 ± 3.8 years. The graft function was preserved (shortening fraction 36 ± 7%), despite an increased number of early rejection episodes (1.7 ± 1.6 vs. 0.7 ± 1.3, overall transplant population, p < 0.05) and hemodynamically comprising rejection episodes (1.3 ± 1.9 vs. 0.7 ± 1.3, overall transplant population, p < 0.05).ConclusionsOverall survival was 54%, with all patients surviving to at least 3 years after undergoing transplantation. None of the children requiring >4 days of ECMO support survived. Despite an increased number of early and hemodynamically compromising rejections, the long-term graft function is similar to our overall transplantation population.

1.1. Document Development Process The Society of Pediatric Cardiology Training Program Directors (SPCTPD) board assembled a Steering Committee that nominated 2 chairs, 1 SPCTPD Steering Committee member, and 5 additional members from a wide range of program sizes, geographic regions, and subspecialty focuses. Representatives from the American College of Cardiology (ACC), American Academy of Pediatrics (AAP), and American Heart Association (AHA) participated. The Steering Committee member was added to provide perspective to each Task Force as a “nonexpert” in that field. Relationships with industry and other entities were not deemed relevant to the creation of a general cardiology training statement; however, employment and affiliation information for authors and peer reviewers are provided in Appendixes 1 and 2, respectively, along with disclosure reporting categories. Comprehensive disclosure information for all authors, including relationships with industry and other entities, is available as an online supplement to this document. The writing committee developed the document, approved it for review by individuals selected by the participating organizations (Appendix 2), and addressed their comments. The final document was approved by the SPCTPD, AAP, and AHA in February 2015 and approved by the ACC in March 2015. This document is considered current until the SPCTPD revises or withdraws it. ### 1.2. Background and Scope The availability of effective pharmacological and surgical treatments for children with pulmonary hypertension (PH) or advanced heart failure has grown rapidly over the past decade.1–3 Although the care of children with these diseases is often coordinated by specialized centers, pediatric cardiologists are increasingly called upon to evaluate and participate in the care of children with PH or advanced heart failure and those who have undergone thoracic organ transplantation. Thus, core training in pediatric cardiology must include sufficient clinical exposure and didactic opportunities for the trainee to gain competency in the evaluation and management of children with these diseases. …