Effect of phosphodiesterase-5 inhibition on SystEmic Right VEntricular size and function. A multicentre, double-blind, randomized, placebo-controlled trial: SERVE.

AIMS: In adults with congenital heart disease and systemic right ventricles, progressive right ventricular systolic dysfunction is common and is associated with adverse outcomes. Our aim was to assess the impact of the phosphodiesterase-5-inhibitor tadalafil on right ventricular systolic function. METHODS AND RESULTS: This was a double-blind, randomized, placebo-controlled, multicentre superiority trial (NCT03049540) involving 100 adults with systemic right ventricles (33 women, mean age: 40.7 ± 10.7 years), comparing tadalafil 20 mg once daily versus placebo (1:1 ratio). The primary endpoint was the change in right ventricular end-systolic volume after 3 years of therapy. Secondary endpoints were changes in right ventricular ejection fraction, exercise capacity and N-terminal pro-B-type natriuretic peptide concentration. Primary endpoint assessment by intention to treat analysis at 3 years of follow-up was possible in 83 patients (42 patients in the tadalafil group and 41 patients in the placebo group). No significant changes over time in right ventricular end-systolic volumes were observed in the tadalafil and the placebo group, and no significant differences between treatment groups (3.4 ml, 95% confidence interval -4.3 to 11.0, p = 0.39). No significant changes over time were observed for the pre-specified secondary endpoints for the entire study population, without differences between the tadalafil and the placebo group. CONCLUSIONS: In this trial in adults with systemic right ventricles, right ventricular systolic function, exercise capacity and neuro-hormonal activation remained stable over a 3-year follow-up period. No significant treatment effect of tadalafil was observed. Further research is needed to find effective treatment for improvement of ventricular function in adults with systemic right ventricles.

Medication in adults after atrial switch for transposition of the great arteries: clinical practice and recommendations.

AIMS: Heart failure is the main threat to long-term health in adults with transposition of the great arteries (TGA) corrected by an atrial switch operation (AtrSO). Current guidelines refrain from recommending heart failure medication in TGA-AtrSO, as there is insufficient data to support the hypothesis that it is beneficial. Medication is therefore prescribed based on personal judgements. We aimed to evaluate medication use in TGA-AtrSO patients and examine the association of use of renin-angiotensin-aldosterone system (RAAS) inhibitors and ß-blockers with long-term survival. METHODS AND RESULTS: We identified 150 TGA-AtrSO patients [median age 30 years (interquartile range 25-35), 63% male] included in the CONCOR registry from five tertiary medical centres with subsequent linkage to the Dutch Dispensed Drug Register for the years 2006-2014. Use of RAAS inhibitors, ß-blockers, and diuretics increased with age, from, respectively, 21% [95% confidence interval (CI) 14-40], 12% (95% CI 7-21), and 3% (95% CI 2-7) at age 25, to 49% (95% CI 38-60), 51% (95% CI 38-63), and 41% (95% CI 29-54) at age 45. Time-varying Cox marginal structural models that adjusted for confounding medication showed a lower mortality risk with use of RAAS inhibitors and ß-blockers in symptomatic patients [hazard ratio (HR) = 0.13 (95% CI 0.03-0.73); P = 0.020 and HR = 0.12 (95% CI 0.02-0.17); P = 0.019, respectively]. However, in the overall cohort, no benefit of RAAS inhibitors and ß-blockers was seen [HR = 0.93 (95% CI 0.24-3.63); P = 0.92 and HR = 0.98 (0.23-4.17); P = 0.98, respectively]. CONCLUSION: The use of heart failure medication is high in TGA-AtrSO patients, although evidence of its benefit is limited. This study showed lower risk of mortality with use of RAAS inhibitors and ß-blockers in symptomatic patients only. These findings can direct future guidelines, supporting use of RAAS inhibitors and ß-blockers in symptomatic, but not asymptomatic patients.

Elective Non-Urgent Balloon-Atrial Septostomy in Infants with d-Transposition of the Great Arteries Does Not Eliminate the Need for PGE1 Therapy at the Time of Arterial Switch Operation.

Once a mainstay in the treatment of neonates with d-transposition of the great arteries (d-TGA), the application of balloon atrial septostomy (BAS) in the d-TGA population has become more selective. Currently, there is no clear evidence for or against a selective BAS strategy. The aims of this single-center retrospective study were to determine the incidence of BAS in the neonatal d-TGA population in the current era, to measure the rate of procedural success, and to compare the outcomes and complication rates of patients who underwent BAS to those who underwent neonatal ASO alone. Between 2012 and 2018, 147 patients with d-TGA underwent initial medical management and ASO, 73 of which underwent BAS. The percentage of patients that underwent BAS decreased from 73 to 33% over the study time period. In patients with d-TGA with intact ventricular septum, 33% of patients remained off of PGE1 at the time of surgery regardless of BAS. In d-TGA with ventricular septal defect, 85.7% of those that underwent BAS and 54.1% of those who did not remained off of PGE1 at the time of surgery, however, this difference did not reach statistical significance. In this single institution retrospective cohort of patients with d-TGA, the performance of a technically successful balloon atrial septostomy did not eliminate the need for PGE1 therapy at the time of definitive ASO. This was true regardless of the presence or absence of a ventricular septal defect.

Aortopulmonary window with pumonary atresia with ventricular septal defect with D-transposition of great arteries: extremely rare anomaly.

Aortopulmonary window (APW) is rare a congenital heart disease accounting for 0.1%-0.2% of all congenital heart defects. The 35% of the APW has been associated with wide variety of other structural heart diseases such as ventricular septal defect, persistent ductus arteriosus, arch anomalies and coronary artery anomalies. To the best of our knowledge, only six cases of APW with pulmonary atresia with ventricular septal defect has been described in the literature. It resembles the type 1 truncus arteriosus, and differentiation from this condition is important prior to surgical correction. We present a case of 14-year-old girl child; she was diagnosed with APW with pulmonary atresia with ventricular septal defect and D transposition of great arteries with the help of echocardiography, cardiac catheterisation and cardiac CT.

Effect of phosphodiesterase-5 inhibition with Tadalafil on SystEmic Right VEntricular size and function - A multi-center, double-blind, randomized, placebo-controlled clinical trial - SERVE trial - Rational and design.

BACKGROUND: Patients with a systemic right ventricle (RV) have a compromised late outcome caused by ventricular dysfunction. Standard medical heart failure therapy has not been shown to improve RV function and survival in these patients. Phosphodiesterase (PDE)-5 inhibition increases contractility in experimental models of RV hypertrophy, but not in the normal RV. In clinical practice, the effects of PDE-5 inhibition on systemic RV function and exercise capacity in adults with a systemic RV have not been tested. METHODS: The SERVE protocol is a double-blind, randomized placebo-controlled multicenter superiority trial to study the effect of PDE-5 inhibition with Tadalafil on RV volumes and function in patients with either D-transposition of the great arteries repaired with an atrial switch procedure or with congenitally corrected transposition of the great arteries. Tadalafil 20mg or placebo will be given over a study period of 3years. The primary endpoint is the change in mean end-systolic RV volumes from baseline to study end at 3years of follow-up (or at the time of permanent discontinuation of the randomized treatment if stopped before 3- years of follow-up), and will be measured by cardiovascular magnetic resonance imaging (CMR) or by cardiac computed tomography in patients with contraindications for CMR. Secondary endpoints are changes in RV ejection fraction, VO2max and NT-proBNP. CONCLUSION: The objective of this study is to assess the effect of PDE-5 inhibition with Tadalafil on RV size and function, exercise capacity and neurohumoral activation in adults with a systemic RV over a 3-year follow-up period.

Preoperative factors as a predictor for early postoperative outcomes after repair of congenital transposition of the great arteries.

Transposition of the great arteries (TGA) requires early surgical repair during the neonatal period. Several preoperative factors have been identified for the postoperative poor outcome after arterial switch operation (ASO). However, the data remain uncertain an association. Therefore, we investigated the preoperative factors which affect the early postoperative outcomes. Between March 2005 and May 2012, a retrospective study was performed which included 126 infants with an ASO for TGA. Preoperative data included the vasoactive inotropic score (VIS) and baseline hemodynamics. Early postoperative outcomes included the duration of mechanical ventilation, the length of stay in the intensive care unit and hospital, and early mortality. Multivariate linear regression and receiver operating characteristics analysis were performed. The duration of mechanical ventilation was significantly correlated with the preoperative mechanical ventilator support and VIS, and CPB time. On multivariate linear regression analysis, a higher preoperative VIS, preoperative B-type natriuretic peptide (BNP) level, and the CPB time were identified as independent risk factors for delayed mechanical ventilation. Preoperative VIS (OR 1.154, 95 % CI 1.024-1.300) and the CPB time (OR 1.034, 95 % CI 1.009-1.060) were independent parameters predicting early mortality. A preoperative VIS of 12.5 had the best combined sensitivity (83.3 %) and specificity (85.3 %) and an AUC of 0.852 (95 % CI 0.642-1.061) predicted early mortality. Our results suggest that preoperative VIS and BNP can predict the need for prolonged postoperative mechanical ventilation. Moreover, preoperative VIS may be used as a simple and feasible indicator for predicting early mortality.

Inhaled iloprost as a rescue therapy for transposition of the great arteries with persistent pulmonary hypertension of the newborn.

Transposition of the great arteries (TGA) in the newborn combined with persistent pulmonary hypertension was reported previously to occur in 3-12 % of full-term neonates with TGA. Right-to-left shunting at the ductal level causes severe hypoxemia despite prostaglandin infusion and balloon atrial septostomy. Although the introduction of inhaled nitric oxide (iNO) has improved the prognosis, this condition still is associated with high preoperative mortality. This report describes the case of a newborn with TGA and persistent pulmonary hypertension, which was managed successfully with oral sildenafil, iNO, and inhaled iloprost during life-threatening acute pulmonary hypertension, thus preventing the use of extracorporeal membrane oxygenation.

Do predictors exist for a successful withdrawal of preoperative prostaglandin E(1) from neonates with d-transposition of the great arteries and intact ventricular septum?

Prostaglandin E(1) (PGE(1)) is given to neonates with d-transposition of the great arteries (d-TGA) to reduce cyanosis by reopening and maintaining the patency of the ductus arteriosus. To avoid side effects, this medication can be stopped for hemodynamically stable patients after balloon atrial septostomy (BAS). A consecutive series of neonates with d-TGA and an intact ventricular septum (IVS) presenting from 2000 through 2005 was analyzed retrospectively to search for side effects of PGE(1) and to identify predictors for a safe preoperative withdrawal. The medication was stopped for hemodynamically stable patients with transcutaneous oxygen saturations higher than 80% after BAS and reinitiated for patients with an oxygen saturation lower than 65%. Patients successfully weaned were compared with those who had failed weaning in terms of atrial septal defect (ASD) size, ductus arteriosus size, and the transcutaneous oxygen saturation. Prostaglandin E(1) was initiated for all 43 neonates with d-TGA. The median maintenance dose of PGE(1) was 0.00625 µg/kg/min (range, 0.00313-0.050 µg/kg/min) for a median duration of 6 days (range, 1-12 days). For 16 patients, PGE(1) was preoperatively withdrawn but then had to be reinitiated for 7 of the 16 patients. No predictors for a successful weaning of PGE(1) were found based on ASD size, ductus arteriosus size, or oxygen saturation. The adverse effects of PGE(1) were apnea in 10 patients and fever in 19 patients. Neither seizures nor necrotizing enterocolitis was documented. Prostaglandin E(1) was successfully withdrawn for a minority of hemodynamically stable patients with d-TGA. No predictors for a successful weaning could be identified. Because apnea and fever are common side effects, withdrawal of PGE(1) after BAS may improve patient safety and comfort. In this patient group, if PGE(1) withdrawal was not well tolerated, it could be safely reinitiated. There were no serious side effects of PGE(1.).

Prostaglandin E2 after septostomy for simple transposition.

In simple transposition of the great arteries (sTGA), balloon atrial septostomy is performed prior to arterial switch to improve mixing of systemic and pulmonary circulations. Following septostomy, some patients are also given prostaglandin E2 (PGE2) until surgical repair. The aims of our study were to identify how often PGE2 is given after septostomy, the indications for starting PGE2, and the effect this has on postoperative outcome. The study was a retrospective review of infants born with sTGA between 2000 and 2005, who underwent arterial switch at Yorkhill Children's Hospital, Glasgow. Over a 5-year period, 26 infants (16 male) with sTGA underwent septostomy. There was a significant rise in mean oxygen saturation following septostomy (mean, 61.4 +/- 11.5% before, 81.5 +/- 9.4% after; p < 0.05). Four of 26 (15%) did not receive PGE2 at all (group 1) and 8 of 26 (30%) received PGE2 before but not after septostomy (group 2). A total of 14 of 26 infants (54%) were given PGE2 following septostomy. This comprised 11 who received PGE2 before and after septostomy (group 3) and 3 who did not receive PGE2 prior to septostomy but did after (group 4). Groups 2 and 3 were compared directly, as they both received PGE2 before septostomy. In group 3, oxygen saturations were lower when PGE2 was started compared with saturations immediately after septostomy (45 +/- 23.6% vs. 80 +/- 10.3%; p < 0.05). Groups 2 and 3 showed no difference in atrial gap after septostomy (9.4 +/- 3 vs. 8 +/- 1 mm; p > 0.05). Fifty percent of infants in group 3 underwent echocardiography prior to restarting PGE2, which revealed a patent arterial duct in all but one patient. Despite PGE2, Group 3 had lower saturations at arterial switch compared with Group 2 (71 +/- 14% vs. 82 +/- 8%; p < 0.05). No difference was observed between group 2 and group 3 with regard to length of cardiopulmonary bypass (group 2, 173 +/- 101.4 min, vs. group 3, 157.9 +/- 42.1 min; p > 0.05). However, the Intensive Care Unit stay was longer for patients who received PGE2 following septostomy (8.5 +/- 10.3 vs. 5 +/- 0.93 days; p < 0.05). Total postoperative stay was also longer for infants who received PGE2 after septostomy (26.8 +/- 14.3 vs. 16.8 +/- 6.3 days; p < 0.05). In conclusion, the use of pulse oximetry has led to an increase in the administration of PGE2 after septostomy. PGE2 administration was associated with a longer ICU stay. The association between administration of PGE2 and longer postoperative stay supports the approach of early surgical repair with minimal preoperative medical intervention.

Multiple brain abscesses in a child with congenital cyanotic heart disease.

We report multiple and diffuse supratentorial and infratentorial brain abscesses in a ten months old girl with D- transposition of great arteries. The child was managed medically with intravenous antibiotics for 4 weeks. Her fever settled, however, weakness of right half of the body persisted despite remarkable improvement. Multiple abscesses (about 40 in number), in a child less than 2 years age, associated neutrophilia with toxic granulations and successful therapy with antibiotics alone makes this an unusual case.

Phentolamine as a treatment for poor mixing in transposition of the great arteries with adequate intraatrial communication.

Patients with transposition of the great arteries often show poor mixing for different reasons, even after adequate balloon atrial septostomy. We present a patient with such a lesion whose clinical status improved dramatically after phentolamine was applied. We believe this improvement is due to reduction in afterload caused by the alpha(2) blocker and also possibly as a response to a presumptive effect of the drug on the diastolic function of the right ventricle, allowing more left-to-right shunt across the atrial septal defect. Both phenomena can improve cardiac output in such a situation.

Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial.

BACKGROUND: Pharmacological blockade of the renin-angiotensin system improves exercise tolerance in patients with left ventricular dysfunction, yet its impact on patients with systemic right ventricles (RVs) remains unknown. METHODS AND RESULTS: A multicenter, randomized, double-blind, placebo-controlled, crossover clinical trial was performed to assess the effects of losartan on exercise capacity and neurohormonal levels in patients with systemic RVs. Of 29 patients studied (age, 30.3+/-10.9 years), 21 had transposition of the great arteries with a Mustard baffle, and 8 had congenitally corrected transposition of the great arteries. Baseline values were as follows: VO2max, 29.8+/-5.6 mL.kg(-1).min(-1) (73.5+/-12.9% predicted value); RV ejection fraction, 41.6+/-9.3%; N-terminal pro brain natriuretic peptide (NT-proBNP), 257.7+/-243.4 pg/mL (normal <125 pg/mL); and angiotensin II, 5.7+/-4.9 pg/mL (normal <5.0 pg/mL). Comparing losartan to placebo showed no differences in VO2max (29.9+/-5.4 versus 29.4+/-6.2 mL.kg(-1).min(-1); P=0.43), exercise duration (632.3+/-123.0 versus 629.9+/-140.7 seconds; P=0.76), and NT-proBNP levels (201.2+/-267.8 versus 229.7+/-291.5 pg/mL; P=0.10), despite a trend toward increased angiotensin II levels (15.2+/-13.8 versus 8.8+/-12.5 pg/mL; P=0.08). CONCLUSIONS: In adults with systemic RVs, losartan did not improve exercise capacity or reduce NT-proBNP levels. Minimal baseline activation of the renin-angiotensin system may explain this lack of benefit and imply an alternative pathophysiological mechanism for the progressive ventricular dysfunction and impaired exercise capacity observed in such patients.

The harlequin color change and association with prostaglandin E1.

The harlequin color change is an unusual cutaneous phenomenon observed in newborn infants as transient, benign episodes of a sharply demarcated erythema on half of the infant, with simultaneous contralateral blanching. In this report, two newborns with congenital heart anomalies demonstrated the harlequin color change, one whose skin findings showed a course related to the dose of systemic prostaglandin E1, suggesting a possible association. The benign, self-limited nature of the color change mandates that prostaglandin E1 not be discontinued for this reason. The entity is likely more common than the paucity of reports in the world literature suggests, and all physicians should recognize its graphic appearance to avoid unnecessary exposure to agents in an effort to treat it.

Pseudo-Bartter syndrome in a neonate on prostaglandin infusion.

UNLABELLED: We describe a case of iatrogenic pseudo-Bartter syndrome caused by administration of prostaglandin E1 (PGE1 alprostadil). Although the use of i.v. PGE1 is a well-established pharmacological therapy in neonates with a ductus-dependent congenital cardiopathy to ensure ductus-dependent flow, we could only find one other report on pseudo-Bartter syndrome related to PGE1 infusion. CONCLUSION: Primary Bartter syndrome is associated with endogenous increased levels of prostaglandins. Therefore, we postulate that the dose of prostaglandin E1 administered, immaturity and the genetic background are all relevant factors involved in the phenotypic presentation of iatrogenic pseudo-Bartter syndrome in this preterm infant.

Improved systemic ventricular function after carvedilol administration in a patient with congenitally corrected transposition of the great arteries.

Congenitally corrected transposition of the great arteries (CCTGA) is associated with shortened survival due, at least in part, to progressive systolic dysfunction of the systemic ventricle. We report a substantial improvement in systemic ventricular function with carvedilol in a 63-year-old man with CCTGA.

[Congenitally corrected transposition of the great vessels in adulthood. The value of noninvasive study methods]. / Kongenital korrigierte Transposition der grossen Arterien im Erwachsenenalter. Wert nicht-invasiver Untersuchungsmethoden.

A 57-year-old man with a cough and increasing exertional dyspnoea for the past 6 weeks was found on examination to have a loud systolic murmur and cardiomegaly with pulmonary congestion. Echocardiography revealed congenitally corrected transposition of the great arteries (cTGA: atrioventricular and ventriculoarterial discordance): a morphologically right ventricle with a tricuspid valve on the left, a morphologically left ventricle with bicuspid a-v valve on the right, the aorta arising ventrally from the left-sided (morphologically right) ventricle. The tricuspid valve showed an Ebstein-like anomaly with obvious regurgitation. Transoesophageal and contrast echocardiography defined valvar anatomy, attachment of the great arteries and cardiac chambers to the venous and arterial circulations, as well as absence of a left to right shunt. Angiography revealed a coronary anatomy typical for cTGA. The exertional dyspnoea responded to diuretics and low doses of ACE inhibitor. Follow-up monitoring of the valvar regurgitation and appropriate endocarditis prophylaxis were recommended. As the haemodynamics in cTGA is normal, in the absence of additional anomalies, it is a congenital cardiac defect which can, though rarely, present first in adulthood. Life expectancy depends on the nature of any additional defects and the degree of commonly associated tricuspid valve regurgitation. As this case demonstrates, echocardiography can largely define the anomalies.

Prostaglandin-induced foveolar hyperplasia simulating pyloric stenosis in an infant with cyanotic heart disease.

Prostaglandin infusion is used to maintain patency of the ductus arteriosus in infants with cyanotic congenital heart disease. Recently, gastric outlet obstruction as a result of prostaglandin infusion has been described. In our case, an upper gastrointestinal contrast study seemed to depict the typical appearance of pyloric stenosis in an infant who had received an infusion of prostaglandin for a prolonged period. Serial ultrasonograms, however, disclosed progressive elongation of the antropyloric channel without wall thickening. This report is the second to illustrate prostaglandin-induced gastric outlet obstruction in a vomiting infant with a gastrointestinal series diagnosis of pyloric stenosis.

Prostaglandin E2 administration in infants with ductus-dependent cyanotic congenital heart disease.

Prostaglandin E2 was administered to 22 newborns with ductus-dependent cyanotic congenital heart disease. Twelve patients had pulmonary atresia and ten simple dextrotransposition of the great arteries. Patients were classified into two groups: group 1 (n = 11) received prostaglandin E2 by the intravenous route (dose: 0.01-0.05 microgram/kg per min); group 2 (n = 11) received prostaglandin E2 by the oral route (dose: 35-65 micrograms/kg per 1-4 h). Treatment lasted for 1-90 days. All infants except one of group 2 showed a significant (greater than 10 Torr) increase in PaO2 following PGE2 administration. The mean increase in PaO2 was higher (P less than 0.01) in group 1 (21.8 +/- 1.7, Torr) than in group 2 (15.8 +/- 1.5, Torr). PaO2 fell significantly (P less than 0.01) in five patients of group 1 who continued treatment orally with satisfactory (greater than 30 Torr) levels in four of them. Severe side effects were observed only in group 1. The data show that similarly to prostaglandin E1 infusions, prostaglandin E2, given i.v. or orally, is useful in the management of infants with ductus-dependent cyanotic congenital heart disease. Oral prostaglandin E2, administration is less effective than i.v. infusions, but can be used for long-term, therapy being more convenient and causing minimal morbidity.