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Background: The effects of levosimendan (Levo) on injury patterns in the immature brain following cardiopulmonary bypass (CPB) are unknown., Methods: Eighteen 3- to 4-wk-old anesthetized lambs, instrumented with vascular catheters and aortic and right carotid artery flow probes, were allocated to non-CPB, CPB, or CPB+Levo groups (each n = 6). After 120 min CPB with 90 min aortic cross-clamp, CPB animals received dopamine, and CPB+Levo animals both dopamine and Levo, for 4 h. All lambs then underwent brain magnetic resonance imaging, followed by postmortem brain perfusion fixation for immunohistochemical studies., Results: In CPB lambs, aortic (P < 0.05) and carotid artery (P < 0.01) blood flows fell by 29 and 30%, respectively, between 2 and 4 h after cross-clamp removal but were unchanged in the CPB+Levo group. No brain injury was detectable with magnetic resonance imaging in either CPB or CPB+Levo lambs. However, on immunohistochemical analysis, white matter astrocyte density of both groups was higher than in non-CPB lambs (P < 0.05), while white matter microglial density was higher (P < 0.05), but markers of cortical oxidative stress were less prevalent in CPB+Levo than CPB lambs., Conclusion: While Levo prevented early postoperative falls in cardiac output and carotid artery blood flow in a lamb model of infant CPB, this was associated with heterogeneous neuroglial activation and manifestation of markers of oxidative stress.

Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.

Meconium aspiration syndrome (MAS) disrupts perinatal decreases in pulmonary vascular resistance (PVR) and is the commonest cause of neonatal pulmonary hypertension. The contribution of the potent vasoactive agent urotensin-II (U-II), in the pathophysiology of this condition, is unknown. In a new perinatal model of MAS, we combined measurement of circulating U-II levels with U-II receptor blockade studies. Nineteen anesthetized lambs were instrumented then randomly allocated to the following groups: 1) control (n = 5), 2) control plus specific U-II receptor blockade with palosuran (n = 5), 3) tracheal instillation of meconium (n = 5), 4) meconium instillation plus palosuran (n = 4). Hemodynamics, PVR, and plasma U-II were measured for 6 h after delivery. After birth in controls, U-II increased (p < 0.05), and PVR fell (p = 0.01) and this fall was prevented by U-II receptor blockade. By contrast, meconium lambs displayed a greater rise in U-II levels (p < 0.05 versus control) with an increase in PVR (p < 0.005) that was attenuated by U-II receptor blockade (p < 0.001). These findings suggest that U-II normally acts as a pulmonary vasodilator after birth, but in the presence of MAS, it assumes a vasoconstrictor role. U-II receptor blockade also improves pulmonary hemodynamics in this model.

Objectives: The aim of this study was to relate changes in energy expenditure and growth in infants with congenital heart disease (CHD), to the timing of corrective cardiac surgery., Methods: Prospective cohort study of infants less than 1 year with CHD admitted for cardiac surgery to Royal Children's Hospital, between January to September 2005. Infants were assessed using anthropometry and indirect calorimetry and compared to healthy age-matched controls., Results: Infants (38) underwent corrective (n=25) or palliative (n=13) cardiac surgery either at < or = 10 days or at >10 days. Infants undergoing corrective surgery after 10 days had deficits in z-scores for weight compared with infants undergoing early surgery (-1.15+/-1.02 vs -0.24+/-0.98; CI 95%: -1.736 to -0.085; P<0.05) and height (-1.47+/-1.16 vs -0.12+/-0.66; CI 95%: -2.262 to -0.428; P<0.01). However, 6 months following surgery, weight and height were similar in both groups. Resting energy expenditure was increased before surgery compared to healthy controls (247+/-36 vs 210+/-22 kJ kg(-1 )day(-1); 95% CI: -57.29 to -16.71; P<0.001) however, normalized 1 week following cardiac surgery. Standard equations did not accurately predict measured REE., Conclusion: Increased REE observed in infants with CHD normalizes within 1 week following corrective cardiac surgery. Deficits in weight and growth were greater in infants undergoing corrective cardiac surgery>10 days of age compared with infants undergoing surgery in the first 10 days of life.

Sildenafil is becoming increasingly popular for the treatment of pulmonary hypertension. However, there are potential concerns regarding its effects on oxygenation and systemic hemodynamics that could theoretically reduce its utility in the neonatal population. We performed a prospective cumulative dose-response study of increasing doses of i.v. sildenafil (0.4, 1, and 3 mg/kg) on hemodynamics and oxygenation in 32 anesthetized piglets, of which 17 had meconium-induced pulmonary hypertension and lung injury, and 15 did not. Sildenafil caused a reduction in mean pulmonary artery pressure and pulmonary vascular resistance (PVR) at all doses, in non-lung-injured animals. There was no difference in pulmonary hemodynamics between doses. Oxygenation index [OI = mean airway pressure (cm H2O) * FiO2 * 100/PaO2 (mm Hg)] did not reach critical levels at any dose. In lung-injured animals, sildenafil also reduced mean pulmonary artery pressure and PVR by 30%. Again, this effect was achieved at the lowest dose, without subsequent changes at higher doses. However, in lung-injured animals, sildenafil produced a dose-related increase in oxygenation index. Sildenafil reduced the systemic vascular resistance (SVR) at the lowest dose in lung-injured animals, but this occurred only at higher doses in non-lung-injured animals. In conclusion, sildenafil is a potent pulmonary vasodilator. However, it should be administered with caution in the presence of lung injury because of a dose-related increase in oxygenation index and concomitant systemic vasodilatation.

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension.

There has been recent interest in the use of the phosphodiesterase-5 inhibitor sildenafil for treating pulmonary hypertension. We examined the interaction between inhaled nitric oxide (iNO) and i.v. sildenafil in 12 piglets with acute pulmonary hypertension and lung injury secondary to meconium aspiration. Six animals (controls) received no intervention after meconium instillation, and six received iNO (20 ppm) from 120 min, with the addition at 240 min of an i.v. sildenafil infusion (2 mg/kg over 2 h). Meconium instillation increased mean pulmonary artery (PA) pressure from 16.0 +/- 3.1 to 24.8 +/- 4.6 mm Hg (p < 0.01) and pulmonary vascular resistance (PVR) from 0.047 +/- 0.008 to 0.089 +/- 0.027 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.01). Oxygenation index increased from 3 +/- 0.8 to 8.3 +/- 3.0 (p < 0.01). There were no further changes beyond 120 min in controls. iNO reduced PA pressure and PVR to baseline values, without influencing oxygenation. The addition of sildenafil further reduced PA pressure, tended to increase the cardiac output, and reduced PVR from 0.049 +/- 0.02 to 0.028 +/- 0.01 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.05). Sildenafil lowered the systemic blood pressure and systemic vascular resistance and produced profound arterial hypoxemia, reducing arterial Po(2) from 69 +/- 23 mm Hg to 49 +/- 15 mm Hg, despite substantial increases first in inspired oxygen fraction and subsequently in mean airway pressures. Consequently, the oxygenation index increased by 13.9 +/- 4.8 (p = 0.01). When given in addition to iNO, sildenafil at a dose of >0.5 mg/kg produced profound pulmonary vasodilation, but this was coupled with an unacceptable deterioration in oxygenation and systemic vasodilation in this model of pulmonary hypertension with acute parenchymal lung disease.

Patients after repair of tetralogy of Fallot are at increased risk of arrhythmic death. Clinical data suggest that pulmonary regurgitation predisposes to these arrhythmias, although the cellular electrophysiologic effects of pulmonary regurgitation are unknown. We induced pulmonary regurgitation in lambs, and 3 mo later, having quantified the pulmonary regurgitant (PR) fraction, studied right ventricular mechanical and electrophysiologic properties in vivo and in vitro. The PR fraction was greater in PR (75 +/- 10%) than in sham-operated animals (8 +/- 4%; p < 0.01). In vivo, monophasic action potential duration and activation time, at rest and during acute right ventricular stretch, were similar in both groups. However, the dispersion of activation time was greater in PR animals at rest (13 +/- 1.1 versus 8 +/- 1.1 ms; p < 0.05). Furthermore, the dispersion of activation increased during right ventricular stretch in PR, but not in sham-operated animals. In vitro, myocardial force-frequency responses were similar in both groups, indicating preserved systolic performance, but mechanical restitution studies showed a prolonged refractory period (447 +/- 22 versus 370 +/- 26 ms; p < 0.05) and a decreased recovery time constant (184 +/- 19 versus 265 +/- 20 ms; p < 0.001) in PR animals, indicating altered calcium cycling. Furthermore, the myocardial conduction velocity was reduced in PR animals (31 +/- 3.58 versus 47.9 +/- 5.1 cm/s; p < 0.01), resulting from a 2-fold increase in intracellular resistance (437.25 +/- 125.93 versus 194 +/- 43.27 Omega. cm; p = 0.025). Chronic PR leads to inhomogeneity of right ventricular activation, alters myocardial calcium cycling, reduces conduction velocity, and increases intracellular resistivity. These may contribute to the development of arrhythmias associated with PR, including those in patients after tetralogy repair.

Little is known about the changes in systemic and pulmonary vascular responses to dobutamine that occur during postnatal development. To address this question, vascular pressures and cardiac output were measured in anesthetized 1- to 2-d-old (n = 6), 7- to 10-d-old (n = 7), and 6- to 8-wk-old lambs (n = 6) while dobutamine was infused incrementally in the dose range of 0.5-40 microg x kg(-1) x min(-1). Dobutamine reduced pulmonary vascular resistance in the three age groups (all p<0.005). However, although this reduction reached a plateau over the infusion range of 15-40 microg x kg(-1) x min(-1) at all ages, its magnitude was less (p<0.02) in 1- to 2-d-old lambs (24+/-2%) than in 7- to 10-d-old (41+/-7%) or 6- to 8-wk-old lambs (42+/-6%). Over the same infusion range, dobutamine produced a fall in systemic vascular resistance (all p<0.005) that was proportionally similar in 1- to 2-d-old (51+/-3%), 7- to 10-d-old (48+/-3%), and 6- to 8-wk-old lambs (42+/-6%). In separate subgroups of 1- to 2-d-old lambs, pulmonary and systemic responses to dobutamine were not affected by pretreatment with selective alpha1-, beta1-, or beta2-adrenoceptor antagonists. Taken together, these findings suggest that the pulmonary but not systemic vasodilator response to dobutamine in lambs is blunted in the initial days after birth, and that this pulmonary effect is not directly related to the adrenoceptor-stimulating properties of dobutamine.