Balloon atrial septostomy for transposition of the great arteries: Safety and experience with the Z-5 balloon catheter.

BACKGROUND: Balloon atrial septostomy (BAS) is an emergent and essential cardiac intervention to enhance intercirculatory mixing at atrial level in deoxygenated patients diagnosed with transposition of the great arteries (TGA) and restrictive foramen ovale. The recent recall of several BAS catheters and the changes in the European legal framework for medical devices (MDR 2017/745), has led to an overall scarcity of BAS catheters and raised questions about the use, safety, and experience of the remaining NuMED Z-5 BAS catheter. AIMS: To evaluate and describe the practice and safety of the Z-5 BAS catheter, and to compare it to the performance of other BAS catheters. METHODS: A retrospective single-center cohort encompassing all BAS procedures performed with the Z-5 BAS catheter in TGA patients between 1999 and 2022. RESULTS: A total of 182 BAS procedures were performed in 179 TGA-newborns at Day 1 (IQR 0-5) days after birth, with median weight of 3.4 (IQR 1.2-5.7) kg. The need for BAS was urgent in 90% of patients. The percentage of BAS procedures performed at bedside increased over time from 9.8% (before 2010) to 67% (2017-2022). Major complication rate was 2.2%, consisting of cerebral infarction (1.6%) and hypovolemic shock (0.5%). The rate of minor complications was 9.3%, including temporary periprocedural AV-block (3.8%), femoral vein thrombosis (2.7%), transient intracardiac thrombus (0.5%), and atrial flutter (2.2%). BAS procedures performed at bedside and in the cardiac catheterization laboratory had similar complication rates. CONCLUSIONS: BAS using the Z-5 BAS catheter is both feasible and safe at bedside and at the cardiac catheterization laboratory with minimal major complications.

Echocardiographic assessment of embryonic and fetal mouse heart development: a focus on haemodynamics and morphology.

BACKGROUND: Heart development is a complex process, and abnormal development may result in congenital heart disease (CHD). Currently, studies on animal models mainly focus on cardiac morphology and the availability of hemodynamic data, especially of the right heart half, is limited. Here we aimed to assess the morphological and hemodynamic parameters of normal developing mouse embryos/fetuses by using a high-frequency ultrasound system. METHODS: A timed breeding program was initiated with a WT mouse line (Swiss/129Sv background). All recordings were performed transabdominally, in isoflurane sedated pregnant mice, in hearts of sequential developmental stages: 12.5, 14.5, and 17.5 days after conception (n = 105). RESULTS: Along development the heart rate increased significantly from 125 ± 9.5 to 219 ± 8.3 beats per minute. Reliable flow measurements could be performed across the developing mitral and tricuspid valves and outflow tract. M-mode measurements could be obtained of all cardiac compartments. An overall increase of cardiac systolic and diastolic function with embryonic/fetal development was observed. CONCLUSION: High-frequency echocardiography is a promising and useful imaging modality for structural and hemodynamic analysis of embryonic/fetal mouse hearts.

30 Years' Experience in Percutaneous Pulmonary Artery Interventions in Transposition of the Great Arteries.

Background: Pulmonary artery (PA) stenosis is common after arterial switch operation (ASO) for transposition of the great arteries (TGA). Differences between balloon angioplasty (BA) and stents on right ventricular (RV) and PA pressures are not well studied. Objectives: The purpose of this study was to analyze percutaneous PA interventions' frequency after ASO, complications, and the effects of BA and stents on RV and PA pressures. Methods: All TGA patients with ASO between 1977 and 2022 in 2 Dutch congenital heart centers were included in this multicenter retrospective study. Peri-operative ASO characteristics and pre-intervention and post-intervention invasive and echocardiographic data were analyzed. Results: ASO was performed in 960 TGA patients, of which 888 survived 30 days and had complete follow-up. Seventy-seven (9%) underwent percutaneous PA interventions. Taussig-Bing anomaly (OR: 2.8; 95% CI: 1.228-6.168; P = 0.014), ASO time era 1990 to 1999 (OR: 4.7; 95% CI: 1.762-12.780; P = 0.002), and 2000 to 2009 (OR: 4.3; 95% CI: 1.618-11.330; P = 0.003) were independently associated with percutaneous PA interventions after ASO. Invasive post-interventional pressures and gradients were lower after stent implantation compared to BA (RV pressure: 47 ± 14 vs 58 ± 11; right PA-PA gradient: 11 ± 11 vs 25 ± 12, P < 0.05; RV/left ventricle pressure ratio: 0.4 ± 0.1 vs 0.6 ± 0.2, P < 0.001). Of the patients with unilateral PA stenosis (left PA: 41%, right PA: 59%), 77% showed increased RV pressure (>30 mm Hg) and RV/left ventricle pressure ratio improved post-intervention (0.5 ± 0.2 vs 0.6 ± 0.2, P < 0.05). Seventeen complications, most minor, were reported (13%). Two post-procedural deaths were reported. Conclusions: Percutaneous PA interventions are common after ASO and can be performed safely but caution for serious complications is warranted. Unilateral PA stenosis can impact RV pressures. Stents may be more successful at treating PA stenosis compared to BA.

Normal and abnormal development of the cardiac conduction system; implications for conduction and rhythm disorders in the child and adult.

The cardiac conduction system is a specialized network that initiates and closely coordinates the heart beat. Cardiac conduction system development is intricately related to the development and maturation of the embryonic heart towards its four-chambered form, as is indicated by the fact that disturbed development of cardiac structures is often accompanied by a disturbed formation of the CCS. Electrophysiological studies have shown that selected conduction disturbances and cardiac arrhythmias do not take place randomly in the heart but rather at anatomical predilection sites. Knowledge on development of the CCS may facilitate understanding of the etiology of arrhythmogenic events. In this review we will focus on embryonic development of the CCS in relation to clinical arrhythmias, as well as on specific cardiac conduction abnormalities that are observed in patients with congenital heart disease.

Accessory atrioventricular myocardial pathways in mouse heart development: substrate for supraventricular tachycardias.

Atrioventricular reentry tachycardia (AVRT) requiring an accessory atrioventricular pathway (AP) is the most common type of arrhythmia in the perinatal period. The etiology of these arrhythmias is not fully understood as well as their capability to dissipate spontaneously in the first year of life. Temporary presence of APs during annulus fibrosus development might cause this specific type of arrhythmias. To study the presence of APs, electrophysiological recordings of ventricular activation patterns and immunohistochemical analyses with antibodies specifically against atrial myosin light chain 2 (MLC-2a), Periostin, Nkx2.5, and Connexin-43 were performed in embryonic mouse hearts ranging from 11.5 to 18.5 days post-conception (dpc). The electrophysiological recordings revealed the presence of functional APs in early (13.5-15.5 dpc) and late (16.5-18.5 dpc) postseptated stages of mouse heart development. These APs stained positive for MLC-2a and Nkx2.5 and negative for Periostin and Connexin-43. Longitudinal analyses showed that APs gradually decreased in number (p = 0.003) and size (p = 0.035) at subsequent developmental stages (13.5-18.5 dpc). Expression of periostin was observed in the developing annulus fibrosus, adjacent to APs and other locations where formation of fibrous tissue is essential. We conclude that functional APs are present during normal mouse heart development. These APs can serve as transient substrate for AVRTs in the perinatal period of development.

Ductal Flow Ratio as Measure of Transition in Preterm Infants After Birth: A Pilot Study.

Background: Cardiovascular changes during the transition from intra- to extrauterine life, alters the pressure gradient across the ductus arteriosus (DA). DA flow ratio (R-L/L-R) has been suggested to reflect the infant's transitional status and could potentially predict neonatal outcomes after preterm birth. Aim: Determine whether DA flow ratio correlates with oxygenation parameters in preterm infants at 1 h after birth. Methods: Echocardiography was performed in preterm infants born <32 weeks gestational age (GA), as part of an ancillary study. DA flow was measured at 1 h after birth. DA flow ratio was correlated with FiO2, SpO2, and SpO2/FiO2 (SF) ratio. The DA flow ratio of infants receiving physiological-based cord clamping (PBCC) or time-based cord clamping (TBCC) were compared. Results: Measurements from 16 infants were analysed (median [IQR] GA 29 [27-30] weeks; birthweight 1,176 [951-1,409] grams). R-L DA shunting was 16 [17-27] ml/kg/min and L-R was 110 [81-124] ml/kg/min. The DA flow ratio was 0.18 [0.11-0.28], SpO2 94 [93-96]%, FiO2 was 23 [21-28]% and SF ratio 4.1 [3.3-4.5]. There was a moderate correlation between DA flow ratio and SpO2 [correlation coefficient (CC) -0.415; p = 0.110], FiO2 (CC 0.384; p = 0.142) and SF ratio (CC -0.356; p = 0.175). There were no differences in DA flow measurements between infants where PBBC or TBCC was performed. Conclusion: In this pilot study we observed a non-significant positive correlation between DA flow ratio at 1 h after birth and oxygenation parameters in preterm infants.

Accessory atrioventricular myocardial connections in the developing human heart: relevance for perinatal supraventricular tachycardias.

BACKGROUND: Fetal and neonatal atrioventricular (AV) reentrant tachycardias can be life-threatening but resolve in most cases during the first year of life. The transient presence of accessory AV myocardial connections during annulus fibrosus development may explain this phenomenon. METHODS AND RESULTS: A total of 45 human embryonic, fetal, and neonatal sectioned hearts (4 to 36 weeks of development) were studied immunohistochemically. Accessory myocardial AV connections were quantified and categorized according to their specific location, and 3D reconstructions were made. Between 4 and 6 weeks of development, the atrial and ventricular myocardium was continuous at the primitive AV canal. At 6 to 10 weeks, numerous accessory myocardial AV connections were identified in the left (45%), right (35%), and septal (20%) regions of the AV junction. Most right-sided accessory connections comprised distinct myocardial strands, whereas left-sided connections consisted of larger myocardial continuities. At 10 to 20 weeks, all accessory AV connections comprised discrete myocardial strands and gradually decreased in number. The majority of accessory connections were located in the right AV junction (67%), predominantly in the lateral aspect (45%). Seventeen percent of the accessory connections were observed in the left AV junction, and 16% were observed in the septal region. 3D reconstructions of the developing AV nodal area at these stages demonstrated multiple AV node-related accessory connections. From 20 weeks until birth, and in neonatal hearts, no further accessory myocardial AV connections were observed. CONCLUSIONS: Isolation of the AV junction is a gradual and ongoing process, and right lateral accessory myocardial AV connections in particular are commonly found at later stages of normal human cardiac development. These transitory accessory connections may act as substrate for AV reentrant tachycardias in fetuses or neonates.

Epicardium-derived cells in development of annulus fibrosis and persistence of accessory pathways.

BACKGROUND: The developmental mechanisms underlying the persistence of myocardial accessory atrioventricular pathways (APs) that bypass the annulus fibrosis are mainly unknown. In the present study, we investigated the role of epicardium-derived cells (EPDCs) in annulus fibrosis formation and the occurrence of APs. METHODS AND RESULTS: EPDC migration was mechanically inhibited by in ovo microsurgery in quail embryos. In ovo ECGs were recorded in wild-type (n=12) and EPDC-inhibited (n=12) hearts at Hamburger-Hamilton (HH) stages 38 to 42. Subsequently, in these EPDC-inhibited hearts (n=12) and in additional wild-type hearts (n=45; HH 38-42), ex ovo extracellular electrograms were recorded. Electrophysiological data were correlated with differentiation markers for cardiomyocytes (MLC2a) and fibroblasts (periostin). In ovo ECGs showed significantly shorter PR intervals in EPDC-inhibited hearts (45+/-10 ms) than in wild-type hearts (55+/-8 ms, 95% CI 50 to 60 ms, P=0.030), whereas the QRS durations were significantly longer in EPDC-inhibited hearts (29+/-14 versus 19+/-2 ms, 95% CI 18 to 21 ms, P=0.011). Furthermore, ex ovo extracellular electrograms (HH 38-42) displayed base-first ventricular activation in 44% (20/45) of wild-type hearts, whereas in all EPDC-inhibited hearts (100%, 12/12), the ventricular base was activated first (P<0.001). Small periostin- and MLC2a-positive APs were found mainly in the posteroseptal region of both wild-type and EPDC-inhibited hearts. Interestingly, in all (n=10) EPDC-inhibited hearts, additional large periostin-negative and MLC2a-positive APs were found in the right and left lateral free wall coursing through marked isolation defects in the annulus fibrosis until the last stages of embryonic development. CONCLUSIONS: EPDCs play an important role in annulus fibrosis formation. EPDC outgrowth inhibition may result in marked defects in the fibrous annulus with persistence of large APs, which results in ventricular preexcitation on ECG. These APs may provide a substrate for postnatally persistent reentrant arrhythmias.

Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development.

BACKGROUND: Identifying molecular pathways regulating the development of pacemaking and coordinated heartbeat is crucial for a comprehensive mechanistic understanding of arrhythmia-related diseases. Elucidation of these pathways has been complicated mainly by an insufficient definition of the developmental structures involved in these processes and the unavailability of animal models specifically targeting the relevant tissues. Here, we report on a highly restricted expression pattern of the homeodomain transcription factor Shox2 in the sinus venosus myocardium, including the sinoatrial nodal region and the venous valves. METHODS AND RESULTS: To investigate its function in vivo, we have generated mouse lines carrying a targeted mutation of the Shox2 gene. Although heterozygous animals did not exhibit obvious defects, homozygosity of the targeted allele led to embryonic lethality at 11.5 to 13.5 dpc. Shox2-/- embryos exhibited severe hypoplasia of the sinus venosus myocardium in the posterior heart field, including the sinoatrial nodal region and venous valves. We furthermore demonstrate aberrant expression of connexin 40 and connexin 43 and the transcription factor Nkx2.5 in vivo specifically within the sinoatrial nodal region and show that Shox2 deficiency interferes with pacemaking function in zebrafish embryos. CONCLUSIONS: From these results, we postulate a critical function of Shox2 in the recruitment of sinus venosus myocardium comprising the sinoatrial nodal region.

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling.

BACKGROUND: Sinus node dysfunction is frequently observed in patients with congenital heart disease (CHD). Variants in the Vascular Endothelial Growth Factor-A (VEGF) pathway are associated with CHD. In Vegf(120/120) mice, over-expressing VEGF120, a reduced sinoatrial node (SAN) volume was suggested. Aim of the study is to assess the effect of VEGF over-expression on SAN development and function. METHODS: Heart rate was measured in Vegf(120/120) and wildtype (WT) embryos during high frequency ultrasound studies at embryonic day (E)12.5, 14.5 and 17.5 and by optical mapping at E12.5. Morphology was studied with several antibodies. SAN volume estimations were performed, and qualitative-PCR was used to quantify expression of genes in SAN tissues of WT and Vegf(120/120) embryos. RESULTS: Heart rate was reduced in Vegf(120/120) compared with WT embryos during embryonic echocardiography (52 ± 17 versus 125 ± 31 beats per minute (bpm) at E12.5, p<0.001; 123 ± 37 vs 160 ± 29 bmp at E14.5, p=0.024; and 177 ± 30 vs 217 ± 34 bmp, at E17.5 p=0.017) and optical mapping (81 ± 5 vs 116 ± 8 bpm at E12.5; p=0.003). The SAN of mutant embryos was smaller and more vascularized, and showed increased expression of the fast conducting gap junction protein, Connexin43. CONCLUSIONS: Over-expression of VEGF120 results in reduced heart rate and a smaller, less compact and hypervascularized SAN with increased expression of Connexin43. This indicates that VEGF is necessary for normal SAN development and function.

Perinatal management and long-term cardiac outcome in fetal arrhythmia.

BACKGROUND: cardiac arrhythmias are commonly observed in the fetus, however, may have major consequences for fetal development and post natal life. AIMS: to evaluate the perinatal management and cardiac outcome of fetuses with tachy- or bradyarrhythmia. STUDY DESIGN: perinatal management, outcome and long-term cardiac follow-up were evaluated retrospectively in consecutive fetuses with cardiac arrhythmias. RESULTS: forty-four fetuses were diagnosed: supraventricular tachycardia (SVT, n=28), atrial flutter (AF, n=7) and atrioventricular block (AVB, n=9). The overall incidence of cardiac anomalies was 18% mainly in the AVB group; hydrops was present in 34%. Direct or transplacental fetal anti-arrhythmic medication was given in 76%. Mortality was 6% in SVT/AF and 78% in the AVB group, respectively. AF resolved in all patients. In the SVT group, Wolff-Parkinson-White (WPW) syndrome was present in 21%, diagnosed at birth or later in life. After the age of one year about 90% of patients in the SVT group remained asymptomatic and free of drugs (median follow-up 76months). CONCLUSIONS: mortality rate is low in patients with fetal SVT and AF but high in patients with AVB. Related morbidity includes WPW-syndrome and congenital cardiac anomalies. Electrocardiographic screening is recommended in all fetal SVT cases before adolescence since WPW-syndrome may occur later in life.

Podoplanin deficient mice show a RhoA-related hypoplasia of the sinus venosus myocardium including the sinoatrial node.

We investigated the role of podoplanin in development of the sinus venosus myocardium comprising the sinoatrial node, dorsal atrial wall, and primary atrial septum as well as the myocardium of the cardinal and pulmonary veins. We analyzed podoplanin wild-type and knockout mouse embryos between embryonic day 9.5-15.5 using immunohistochemical marker podoplanin; sinoatrial-node marker HCN4; myocardial markers MLC-2a, Nkx2.5, as well as Cx43; coelomic marker WT-1; and epithelial-to-mesenchymal transformation markers E-cadherin and RhoA. Three-dimensional reconstructions were made and myocardial morphometry was performed. Podoplanin mutants showed hypoplasia of the sinoatrial node, primary atrial septum, and dorsal atrial wall. Myocardium lining the wall of the cardinal and pulmonary veins was thin and perforated. Impaired myocardial formation is correlated with abnormal epithelial-to-mesenchymal transformation of the coelomic epithelium due to up-regulated E-cadherin and down-regulated RhoA, which are controlled by podoplanin. Our results demonstrate an important role for podoplanin in development of sinus venosus myocardium.

Cardiac malformations and myocardial abnormalities in podoplanin knockout mouse embryos: Correlation with abnormal epicardial development.

Epicardium and epicardium-derived cells have been shown to be necessary for myocardial differentiation. To elucidate the function of podoplanin in epicardial development and myocardial differentiation, we analyzed podoplanin knockout mouse embryos between embryonic day (E) 9.5 and E15.5 using immunohistochemical differentiation markers, morphometry, and three-dimensional reconstructions. Podoplanin null mice have an increased embryonic lethality, possibly of cardiac origin. Our study reveals impairment in the development of the proepicardial organ, epicardial adhesion, and spreading and migration of the epicardium-derived cells. Mutant embryos show a hypoplastic and perforated compact and septal myocardium, hypoplastic atrioventricular cushions resulting in atrioventricular valve abnormalities, as well as coronary artery abnormalities. The epicardial pathology is correlated with reduced epithelial-mesenchymal transformation caused by up-regulation of E-cadherin, normally down-regulated by podoplanin. Our results demonstrate a role for podoplanin in normal cardiac development based on epicardial-myocardial interaction. Abnormal epicardial differentiation and reduced epithelial-mesenchymal transformation result in deficient epicardium-derived cells leading to myocardial pathology and cardiac anomalies.

Nkx2.5-negative myocardium of the posterior heart field and its correlation with podoplanin expression in cells from the developing cardiac pacemaking and conduction system.

Recent advances in the study of cardiac development have shown the relevance of addition of myocardium to the primary myocardial heart tube. In wild-type mouse embryos (E9.5-15.5), we have studied the myocardium at the venous pole of the heart using immunohistochemistry and 3D reconstructions of expression patterns of MLC-2a, Nkx2.5, and podoplanin, a novel coelomic and myocardial marker. Podoplanin-positive coelomic epithelium was continuous with adjacent podoplanin- and MLC-2a-positive myocardium that formed a conspicuous band along the left cardinal vein extending through the base of the atrial septum to the posterior myocardium of the atrioventricular canal, the atrioventricular nodal region, and the His-Purkinje system. Later on, podoplanin expression was also found in the myocardium surrounding the pulmonary vein. On the right side, podoplanin-positive cells were seen along the right cardinal vein, which during development persisted in the sinoatrial node and part of the venous valves. In the MLC-2a- and podoplanin-positive myocardium, Nkx2.5 expression was absent in the sinoatrial node and the wall of the cardinal veins. There was a mosaic positivity in the wall of the common pulmonary vein and the atrioventricular conduction system as opposed to the overall Nkx2.5 expression seen in the chamber myocardium. We conclude that we have found podoplanin as a marker that links a novel Nkx2.5-negative sinus venosus myocardial area, which we refer to as the posterior heart field, with the cardiac conduction system.