Left Pulmonary Artery Blood Flow Research Articles

Acceleration time to Ejection time ratio in fetal pulmonary artery system can predict neonatal respiratory disorders in gestational diabetic mellitus women

Few researches studied fetal pulmonary pulse wave doppler and the clinical end point disorders in gestational diabetic mellitus (GDM) cohort. To investigate fetal pulmonary artery acceleration time to ejection time ratio (PATET) in the prediction of neonatal respiratory disorders (NRD). 238 pregnant women diagnosed with GDM who attended our hospital between February 2018 and March 2020 were retrospectively included. Fetal pulmonary artery Doppler wave measurements were recorded, including main, left and right pulmonary artery blood flow, and left and right peripheral pulmonary artery blood flow. Acceleration time (At)/ejection time (Et) were calculated. 183 GDM pregnant women and neonates were divided into NRD(+)(n = 42) and NRD(-) group (n = 141). 16 cases were neonatal pneumonia (NP) within 28 days after birth in NRD(+) group. The area under curve (AUC) of left peripheral pulmonary artery acceleration time to ejection time (LPPATET) was 0.967 (95% CI: 0.927∼1.000, P < 0.001) and the AUC of right peripheral pulmonary artery acceleration time to ejection time (RPPATET) was 0.967 (95% CI: 0.927∼1.000, P < 0.001), indicating that LPPATET and RPPATET are both predictors for NRD. The results of interobserver variabilty and intraobserver variability showed a good consistency. The At/Et of fetal peripheral pulmonary artery (PPA) in GDM women may be predictors for NRD, and the indicator can provide assistance in clinical management of diabetes pregnant patients.

Impact of maternal late gestation undernutrition on surfactant maturation, pulmonary blood flow and oxygen delivery measured by magnetic resonance imaging in the sheep fetus.

Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero. The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery ( ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140days' gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial compared to control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins (SFTP) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery and to the fetal lung. There was a negative relationship between left pulmonary artery flow and to the left lung with SFTP-B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. KEY POINTS: Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signalling pathways involved in fetal lung development, pulmonary haemodynamics and oxygen delivery in sheep using a combination of molecular and magnetic resonance imaging (MRI) techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial . Surfactant maturation was not affected; however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary haemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with surfactant protein B mRNA and protein expression in late gestation.

Pulmonary Embolism in a Critically Ill Infant with Univentricular Parallel Circulation

AbstractA 3-month-old infant patient with hypoplastic left heart syndrome diagnosed in the prenatal period required long-term intensive care for refractory chylothorax and chylous ascites after undergoing bilateral pulmonary artery banding at age 6 days. Weaning from mechanical ventilation was difficult due to massive edema, and a central venous catheter was required because enteral feeding was hampered by the refractory chyle leakage, for which surgery was ineffective. On the evening after central venous catheter replacement was performed, his respiratory condition suddenly deteriorated; cardiac ultrasound revealed that the left pulmonary arterial blood flow had decreased, and enhanced computed tomography demonstrated a left pulmonary embolism (PE), which was identified as the cause of a sudden decrease in the pulmonary blood flow. The patient died due to refractory septic shock at age 5 months. PEs in children, especially patients with cyanotic congenital heart disease, are difficult to diagnose because of their atypical presentation. Current diagnostic criteria are based on adult guidelines, and a few factors in the criteria, such as tachycardia and hypoxia, are difficult to apply for pediatric cyanotic patients with intracardiac or extracardiac right-to-left shunt. In fact, those criteria have lower specificities in children. In conclusion, the present case suggested that a sudden decrease in the pulmonary blood flow can aid the physicians in diagnosing PE in patients with cyanotic congenital heart disease. We need more pediatric cases and evidence of PE in children to make a PE guideline, which is specific to pediatric patients including cyanotic congenital heart disease.

A new index of ultrasonography for estimating cerebral circulation in newborn infants.

To quantitatively estimate the influence of ductal shunt on cerebral blood flow and establish a new index of ultrasonography for estimating cerebral circulation without the influence of ductal shunt in newborn infants. We retrospectively examined the records of anterior cerebral artery (ACA) and left pulmonary artery (LPA) blood flow velocity curves recorded by pulsed Doppler ultrasonography within 6h after birth in 123 newborn infants without asphyxia (normal group) and in 31 newborn infants with asphyxia (asphyxia group). In the normal group, the resistance index (RI) of the ACA showed a positive correlation with the ratio of LPA diastolic-to-systolic flow velocities (LPAD/LPAS) (P < 0.001, r = 0.58), and the estimated RI (eRI) of the ACA was calculated using the following formula: Y = 0.47X + 0.67 (Y estimated RI; X LPAD/LPAS). In the asphyxia group, the RI of the ACA showed a weak correlation to base excess (BE) (P < 0.05, r = 0.46). The eRI of the ACA was calculated by the LPAD/PLAS in the asphyxia group, and the difference between the RI and eRI showed a better correlation to BE than RI (P < 0.001, r = 0.64). We determined the relation between cerebral blood flow RI and ductal shunt, and (RI - eRI) may be a new useful ultrasonographic index indicating cerebral circulation without the influence of ductal shunt in newborn infants.

Abstract 17145: Outcomes of Transcatheter Occlusion of Patent Ductus Ateriouses in Infants ≤ 6 Mouths

Objectives: We sought to analyze the outcomes of transcatheter patent ductus arteriosus (PDA) occlusion using a variety of devices in infants ≤ 6 mouths and discuss the transcatheter occlusion indication of PDA in early infants. Methods and Results: A total of 72 patients underwent successful transcatheter device closure. The mean age at catheterization was 4.9±1.8months (1-6 months) with a mean weight at catheterization of 5.1±1.9kg (1.9-6.7kg), the mean PDA diameter of 3.9±0.8mm (1.8-5.3mm),the mean systolic pulmonary arteriosus pressure of 55.7±8.9 mmHg (46-79mmHg). Among these suffered infants, companied with 72cases of growth retardation, 48 cases of recurrent lower respiratory tract infection, 35 cases associated with congestive heart failure, and 5 cases of respirator-oxygen-dependent. 4/6-8/10 PDA occluder was selected for transcatheter device closure, and intraoperative blood transfusion were performed in 46 cases. All subjects resulted with occluder position in good shape, no residual shunt; whileas 16 cases with aortic blood flow velocity increased slightly, 12 cases with left pulmonary artery blood flow velocity increased slightly just postoperation. And in follow-ups the increased velocity of and pulmonary blood flow gradually returned to normal. Follow-up data showed, all subjects resulted good outcomes with growth significantly improved, congestive heart failure cured and repeated lower respiratory tract infection significantly reduced postoperative. Conclusions: In experienced heart center, percutaneous closure of PDA should be considered even in infants ≤ 6 mouths. The indications include PDA infants with respirator-oxygen-dependent, congestive heart failure, and recurrent lower respiratory tract infection and growth retardation. Children underwent PDA occlusion would result with improved growth and development, recovered heart function and less lower respiratory tract infection.

Fever, abdominal distension, polyserositis

Objective To provide useful information for the diagnosis and differentiation through exploring the tumor with polyserositis as the initial symptom. Methods There was a case present with fever, poor spirit, abdominal distention and edema in Children′s Hospital of Hebei Province.The characteristics and results of physical examination were summarized and discussed according to the condition evolution phases.The possible etiological factors were analyzed.The treatment was adjusted.Further physical examination was improved.The final diagnosis was tracked. Results After getting admitted to hospital, the patient received CT scan and ultrasound examination for many times.The results suggested the pericardial effusion, pleural effusion, peritoneal effusion and cardiac insufficiency.The child had made a slight improvement through treatment.However, he had hemiparesis.Cerebral infarction was demonstrated through magnetic resonance imaging(MRI), magnetic resonance angiography(MRA), magnetic resonance venography(MRV). Ultrasound showed that there was more pericardial effusion, aortic root solid low echo mass, pulmonary arterial wall stiffness, left and right pulmonary artery blood flow speed increased.Neck and chest enhanced CT showed mediastinal lesions.Pathology examination results suggested myeloid sarcoma after referral to superior hospital. Conclusions When children had an unexplained polyserositis, more comprehensive analysis were needed.The illness condition should be explained with Monism as far as possible.Repeated inspections would be necessary when the pathogenesis was not clear.Careful watch for the tumor should be kept. Key words: Polyserositis; Heart failure; Cerebral infarction; Tumour

Emergency and sub-emergency transcatheter closure of patent ductus arteriosus in infants

Objective To explore the effects and follow-up findings of emergency and sub-emergency transcatheter closure of patent ductus arteriosus (PDA) in infants. Methods A retrospective study was performed to analyze the effects, complications, immediate and mid-term follow-up outcomes in 12 infants with PDA from Guangzhou Women and Children's Medical Center between March 2008 and April 2014 in order to evaluate the efficacy and safety of transcatheter closure of PDA in infants.All cases were diagnosed preoperatively as pneumonia, and 10 cases had congestive heart failure.Pulmonary symptoms showed no obvious change after regular internal medicine therapies. Results Twelve devices (100%) were successfully implanted.Echocardiogram was performed 3 days after the procedures and showed no residual shunt in any case.Left ventricular end-diastolic dimension[(31.3±5.4) mm], left atrial diameter[(18.2±3.4) mm], left ventricular ejection fraction(LVEF)[(56.8±8.7)%], pulmonary artery systolic pressure and mitral regurgitation were decreased or alleviated in contrast with those before the procedures(all P 0.05). Left pulmonary artery blood flow velocity was increased in 3 cases.The maximal descending aorta blood flow velocity was 1.9 m/s and 2.4 m/s respectively in 2 cases, blood flow velocity of left pulmonary artery and descending aorta were blow 2.3 m/s, pressure gradient was less than 2.9 kPa in 23-28 months after the procedure and no patient received any other intervention. Conclusions Emergency and sub-emergency transcat-heter closure of PDA in infants is safe and feasible, but long-term follow-up is needed in patients with increased left pulmonary artery blood flow velocity and/or descending aorta blood flow velocity. Key words: Patent ductus arteriosus; Interventional therapy; Emergency and sub-emergency; Infant

Tracheal occlusion alters pulmonary circulation in the fetal lamb with normally developing lungs

BackgroundTracheal occlusion (TO) promotes fetal lung growth through an increase in intraluminal pressure. Although evidence suggests that fetal TO (FETO) decreases the occurrence of pulmonary hypertension in severe congenital diaphragmatic hernia, controversies on its effect on the pulmonary circulation remain. Therefore, we investigated the effects of FETO on the lung hemodynamics in a chronically catheterized fetal lamb model. MethodsFifteen pregnant ewes were operated on between 125 and 128days of gestation (term: 145days). Catheters and ultrasonic flow transducer were placed through a left thoracotomy in the lamb fetus to determine aortic, pulmonary and left atrial pressures, and left pulmonary artery blood flow. A balloon was positioned between the carina and vocal cords under fetoscopic control. The animals were assigned to either control (n=6) or FETO (n=9) groups. TO was performed by inflating the balloon. We studied the acute effects of temporary (2-h) and prolonged (4-day) TO on basal pulmonary vascular tone and on the pulmonary vascular reactivity to acetylcholine and to increased fetal oxygen tension. ResultsWe found that left pulmonary blood flow (LPA) increased and pulmonary vascular resistance (PVR) decreased by 20% during brief TO (p<0.05). After balloon deflation, LPA blood flow further increased by 40%, and PVR decreased by 50% compared to baseline values (p<0.05). In contrast, no change in LPA blood flow or PVR was observed during prolonged TO. Moreover, the vasodilator responses to acetylcholine and to increased fetal PaO2 were blunted during TO. ConclusionsThese data indicate that antenatal tracheal occlusion promotes active pulmonary vasodilation, which is partly blunted by the mechanical effects of elevation of the intraluminal pressure.

236: Effects and mechanisms of n-3 polyunsaturated fatty acids in the fetal pulmonary circulation

The effect of n-3 polyunsaturated fatty acids in the pulmonary circulatory is not well defined. This question is clinically relevant in respiratory failure associated with pulmonary hypertension. To investigate this effect we have realised a randomized, placebo-controlled comparative study on sixty-two chronically prepared lamb fetuses. Catheters and ultrasonic flow transducer were placed through a left thoracotomy in the lamb fetus to determine aortic, pulmonary, and left atrial pressures and left pulmonary artery blood flow. We compared the pulmonary vascular responses to 120 min of Omegaven (lipid emulsions enriched in n-3 polyunsaturated fatty acids) or Intralipide (lipid emulsions enriched in n-6 polyunsaturated fatty acids) infusion. Then we investigated the effects of Omegaven on the pulmonary circulation after nitric oxide synthase inhibition by L-nitro-arginine, potassium channel blockade by tetraethylammonium, cytochrome P450 epoxygenase inhibition by (methylsulfonyl)-2- (2-propynyloxy)-benzenehexanamide, and cyclo-oxygenase inhibition by Ibuprofen. Pulmonary artery and aortic pressures as well as blood gases and plasma lactate concentrations did not change during either fat emulsion infusion. Left pulmonary blood flow increased by 30% and pulmonary vascular resistance decreased by 28% during Omegaven infusion, whereas they did not change during Intralipide infusion. This pulmonary vascular response to Omegaven was not altered by l-nitro-arginine or Ibuprofen infusion. At the opposite, Omegaven induced pulmonary vasodilatation was abolished by tetraethylammonium and markedly attenuated by (methylsulfonyl)-2- (2-propynyloxy)-benzenehexanamide. Lipid emulsion containing n-3 polyunsaturated fatty acids may induce a potent and sustained vasodilatation in the fetal lung. This pulmonary vasodilator response is mediated through production of vasoactive mediators by cytochrome P450 epoxygenase and through activation of potassium channels.

Impaired Lung Function After Intubation and Mechanical Ventilation for Surgical Ligation of the Ductus Arteriosus in Preterm Infants

Significant patent ductus arteriosus (PDA) in the preterm infant has been associated with pulmonary edema and impaired gas exchange. Therefore, surgical ligature of the DA may be required. However, the effects of intubation and mechanical ventilation on the PDA-induced lung dysfunction presently are unknown. The aim of the study was to investigate whether intubation and mechanical ventilation alter pulmonary function in the preterm infant with significant PDA. A prospective study. The neonatal intensive care unit and department of anesthesiology in a university hospital. Preterm infants <32 weeks' gestational age treated with nasal continuous positive airway pressure (NCPAP) and requiring mechanical ventilation for undergoing surgical DA ligature. Respiratory, Doppler echocardiographic parameters, and chest x-ray transparencies of the lungs were measured during NCPAP and 2 hours after intubation and starting mechanical ventilation. Twenty preterm infants (gestational age = 27 ± 1 wk, birth weight = 950 ± 140 g) were included. Heart rate, O(2) need, PaCO(2), and plasma lactate concentrations were significantly higher after intubation. The mean oxygenation index increased from 1.5 ± 0.6 to 7.2 ± 3 (p < 0.05). The overall transparencies of the lungs decreased after intubation. DA diameter, shortening fraction of the left ventricle, left pulmonary artery blood flow velocities, and left atrium/aorta did not change. In preterm infants with significant PDA, intubation and mechanical ventilation before surgical DA ligation may increase the O(2) need and PaCO(2) and may promote lung edema formation. Mechanical ventilation-induced impairment in lung function is not associated with a change in pulmonary or systemic circulation or DA flow. Special care should be taken to prevent respiratory failure when intubation and mechanical ventilation are required for undergoing surgical DA ligation in the preterm infant.

Exercise Testing and Training in Children With Congenital Heart Disease

The primary function of the cardiopulmonary system is to provide blood flow (and oxygen) in quantities sufficient to support the metabolic needs of the body. The capacity of the cardiopulmonary system to fulfill this function is maximally stressed when an individual's metabolic rate is increased, a condition that occurs most commonly during physical activity/exercise. A number of physiological changes accompany and facilitate the accommodation of the circulatory system to the hemodynamic demands of exercise (Figure 1). In normal individuals, these changes (which during upright exercise include a tripling of the resting heart rate, a >60% reduction in systemic and pulmonary vascular resistance, and a >50% increase in stroke volume) can ultimately produce a >5-fold increase in cardiac output. The increase in cardiac output is accompanied by enhanced ventricular preload (as the ventricles move up their Starling curves to accommodate the increased workload), a doubling of systolic and mean pulmonary artery pressures (most of the increase in pulmonary artery pressures is due to the concomitant rise in left-sided filling pressures; the increase in transpulmonary pressure gradient is relatively small), and a more modest increase in systemic arterial pressures.1,–,4 Figure 1. Some of the physiological changes that accompany and facilitate the accommodation of the circulatory system to the hemodynamic demands of exercise. RAp indicates right atrial pressure; LAp, left atrial pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; PAp, pulmonary artery pressure; and AOp, aortic pressure. Congenital heart disease (CHD) may, in a variety of ways and to a variable extent, adversely affect these hemodynamic adaptations. For instance, patients with a Fontan procedure lack a pulmonary ventricle. They therefore cannot increase their pulmonary blood flow and pressures normally (and consequently cannot maintain their ventricular preload and systemic blood flow) during exercise.5 Patients with tetralogy of Fallot and …

Fasudil inhibits the myogenic response in the fetal pulmonary circulation

In addition to high pulmonary vascular resistance (PVR) and low pulmonary blood flow, the fetal pulmonary circulation is characterized by mechanisms that oppose vasodilation. Past work suggests that high myogenic tone contributes to high PVR and may contribute to autoregulation of blood flow in the fetal lung. Rho-kinase (ROCK) can mediate the myogenic response in the adult systemic circulation, but whether high ROCK activity contributes to the myogenic response and modulates time-dependent vasodilation in the developing lung circulation are unknown. We studied the effects of fasudil, a ROCK inhibitor, on the hemodynamic response during acute compression of the ductus arteriosus (DA) in chronically prepared, late-gestation fetal sheep. Acute DA compression simultaneously induces two opposing responses: 1) blood flow-induced vasodilation through increased shear stress that is mediated by NO release and 2) stretch-induced vasoconstriction (i.e., the myogenic response). The myogenic response was assessed during acute DA compression after treatment with N(omega)-nitro-L-arginine, an inhibitor of nitric oxide synthase, to block flow-induced vasodilation and unmask the myogenic response. Intrapulmonary fasudil infusion (100 microg over 10 min) did not enhance flow-induced vasodilation during brief DA compression but reduced the myogenic response by 90% (P<0.05). During prolonged DA compression, fasudil prevented the time-dependent decline in left pulmonary artery blood flow at 2 h (183+/-29 vs. 110+/-11 ml/min with and without fasudil, respectively; P<0.001). We conclude that high ROCK activity opposes pulmonary vasodilation in utero and that the myogenic response maintains high PVR in the normal fetal lung through ROCK activation.

Hypotension in Preterm Infants with Significant Patent Ductus Arteriosus: Effects of Dopamine

To study the effects of dopamine on systemic arterial pressure (SAP) and systemic blood flow (SBF) (estimated with the superior vena cava [SVC] flow) in preterm infants with hypotension and patent ductus arteriosus (PDA). Clinical and echocardiographic variables were measured before and 2 hours after starting dopamine in premature infants <32 weeks gestational age with PDA and systemic hypotension. Seventeen premature infants were included (gestational age, 28+/-2 weeks; birth weight, 1030 +/- 400 g). A mean rate of 8 +/- 2 microg/kg/min of dopamine raised SAP from 30 +/- 3 to 41 +/- 5 mm Hg (P < .05), and the pulmonary artery pressures from 25 +/- 5 to 32 +/- 8 mm Hg (P < .05). The SVC flow increased by 30% (from 130 +/- 40 to 170 +/- 44 mL/kg/min; P < .05). The left ventricular output and the end-diastolic and mean left pulmonary artery blood flow velocities did not change despite the increase in pulmonary artery pressure. In preterm infants with hypotension and PDA, dopamine (<10 microg/kg/min) increases the systemic blood pressure and the systemic blood flow. Our results suggest that dopamine decreases left-to-right shunting across ductus arteriosus, caused by a rise in pulmonary vascular resistances.

Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension

To evaluate the respiratory and the pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension (PPHN)-induced cardiac dysfunction. Inclusion criteria were: 1) Newborn infants >35 weeks gestational age; 2) PPHN treated with inhaled nitric oxide; and 3) symptoms of circulatory failure despite adequate fluid resuscitation. Lung function and pulmonary hemodynamic variables assessed with Doppler echocardiography were recorded prospectively before and after starting norepinephrine. Eighteen newborns were included (gestational age: 37 +/- 3 weeks; birth weight: 2800 +/- 700 g). After starting norepinephrine, systemic pressure and left ventricular output increased respectively from 33 +/- 4 mm Hg to 49 +/- 4 mm Hg and from 172 +/- 79 mL/kg/min to 209+/-90 mL/kg/min (P < .05). Although the mechanical ventilatory variables have not been changed, the post-ductal transcutaneous arterial oxygen saturation increased from 89% +/- 1% to 95% +/- 4%, whereas the oxygen need decreased from 51% +/- 24% to 41% +/- 20% (P < .05). The pulmonary/systemic pressure ratio decreased from 0.98 +/- 0.1 to 0.87 +/- 0.1 (P < .05). Mean left pulmonary artery blood flow velocity increased by 20% (P < .05). Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary/systemic artery pressure ratio and improved cardiac performance.

Effects of BAY 41–2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus

Nitric oxide (NO)-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41-2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41-2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125-130 days gestation; term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Pulmonary vascular resistance (PVR) was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41-2272 caused dose-related increases in pulmonary blood flow up to threefold above baseline and reduced PVR by 75% (P < 0.01). Prolonged infusion of BAY 41-2272 caused sustained pulmonary vasodilation throughout the 120-min infusion period. The pulmonary vasodilator effect of BAY 41-2272 was not attenuated by N(omega)-nitro-l-arginine, a NO synthase inhibitor. In addition, compared with sildenafil, a phosphodiesterase 5 inhibitor, the pulmonary vasodilator response to BAY 41-2272 was more prolonged. We conclude that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation independent of NO release. We speculate that BAY 41-2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production.

Endothelin B Receptor Blockade Attenuates Pulmonary Vasodilation in Oxygen-Ventilated Fetal Lambs

Background: Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ET_A and ET_B. ET_A receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ET_B receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ET_B receptors contributes to the fall in pulmonary vascular tone at birth is unknown. Objective and Methods: To determine the role of acute ET_B receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ET_B receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO₂ (100%) in near-term fetal sheep. Results: Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO₂ ventilation (p < 0.001 vs. control for each FiO₂ concentration). PVR progressively decreased during mechanical ventilation with low and high FiO₂ in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p < 0.001). Conclusions: We conclude that selective ET_B receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ET_B receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.

Noninvasive assessment of fetal pulmonary blood flow in experimental pulmonary hypertension in the fetal lamb.

The aim of this study was to assess pulmonary arterial blood flow changes induced by the creation of a systemic arteriovenous fistula (120 d gestation) in the fetal lamb using Doppler technique. Doppler echocardiographic assessment of the pulmonary artery blood flow performed 1, 6, and 14 d after surgery showed that mean pulmonary arterial blood flow in the left or right pulmonary artery was 224 +/- 58 mL/min at day 1 in the fistula group, significantly higher than in the control group (113 +/- 22 mL/min; p < 0.01, ANOVA test) whether no difference was found at days 6 and 14. The mean inner diameter of the left pulmonary artery measured on postmortem lung arteriograms compared favorably to the one measured on day 14 at the same level on ultrasound. The mean left pulmonary arterial blood flow, measured at birth on day 14 after surgery, using ultrasonic flow transducer, was not statistically different from the one measured by Doppler on day 14. Our data demonstrate that echocardiography allows accurate assessment of pulmonary arterial blood flow in utero, providing evidence suggesting transient high pulmonary blood flow that did not last >6 d after the creation of a systemic fistula.

Systemic arteriovenous fistula leads to pulmonary artery remodeling and abnormal vasoreactivity in the fetal lamb.

Several cases of systemic arteriovenous fistula diagnosed in the human fetus have been associated with the postnatal development of persistent pulmonary hypertension. The aim of this study was to determine the effects of a prenatally created systemic arteriovenous fistula on the structure and reactivity of the pulmonary circulation in the fetal lamb. A fistula between the jugular vein and carotid artery was created in fetal lambs at 119-124 days of gestation. At delivery (134-139 days), left pulmonary artery (LPA) pressure was increased in the fistula group (n = 12) compared with controls (n = 11, P < 0.01). The pulmonary vascular resistance was significantly higher in the fistula group (P < 0.05), whereas mean LPA blood flow was not statistically different between the two groups. Morphometric analysis of the pulmonary vascular bed revealed an increase in the number of peripheral muscular arteries, together with an increase in pulmonary arterial medial thickness in the fistula group. There was no difference in the relative number or size of intraacinar arteries. In vitro organ bath studies on pulmonary arterial rings showed impaired endothelium-dependent relaxation in the fistula group compared with controls. However, endothelial nitric oxide synthase protein expression was similar in both groups, whereas endothelium-independent relaxation to sodium nitroprusside was greater in the fistula group compared with controls. A systemic arteriovenous fistula leads to both structural and functional alteration of the pulmonary vasculature, which might lead to the development of persistent pulmonary hypertension after birth.

Non-Anti-Galα1-3Gal Antibody Mechanisms Are Sufficient to Cause Hyperacute Lung Dysfunction in Pulmonary Xenotransplantation1

Hyperacute lung dysfunction, which is always associated with pulmonary pig-to-primate xenotransplantation is not well understood. The mechanisms associated with its occurrence seem to differ from mechanisms involved in hyperacute xenograft rejection seen in porcine hearts or kidneys transplanted into primates. To determine the contribution of anti-Gal alpha1-3Gal antibodies (alphaGAb) in such a process, we performed a set of orthotopic pig lung transplants into baboons depleted of alphaGAb and compared graft function and survival with those receiving only immunosuppression. Pigs expressing human membrane cofactor protein served as donors. All baboons received triple immunosuppressive therapy. Depletion of alphaGAb in the experimental group (n = 4) was done by way of immunoadsorption using immunoaffinity membranes. Controls (n = 4) did not undergo immunoadsorption. Orthotopic lung transplants were performed through a left thoracotomy. Main pulmonary artery blood flow and pressure, left pulmonary artery blood flow, and left atrial pressure were recorded. At 1 hour after reperfusion, pulmonary artery graft flows and pulmonary vascular resistances (PVR) were better in animals depleted of alphaGAb than in controls (605 +/- 325.2 mL/min versus 230 +/- 21 mL/min; 27.1 +/- 41.3 mmHg/L/min versus 63 +/- 1 mmHg/L/min). But at 3 hours after reperfusion average graft flows in baboons depleted of alphaGAb had decreased to 277.6 +/- 302.2 mL/min and PVRs had increased 58.3 +/- 42.0 mmHg/L/min. On the other hand, controls maintained stable flows and PVRs (223 +/- 23 mL/min; 61 +/- 3 mmHg/L/min). Survival was ultimately better in control baboons when compared with alphaGAb depleted ones (12.2 +/- 3.3 h versus 4.4 +/- 3.2 h). Unlike heart and kidney xenograft transplants, hyperacute lung xenograft dysfunction seems to be mediated by factors other than alphaGAb.

NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation.

Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.