Complex genotype-phenotype correlation of MYH11: new insights from monozygotic twins with highly variable expressivity and outcomes.

BACKGROUND: Thoracic aortic aneurysm/dissection (TAAD) and patent ductus arteriosus (PDA) are serious autosomal-dominant diseases affecting the cardiovascular system. They are mainly caused by variants in the MYH11 gene, which encodes the heavy chain of myosin 11. The aim of this study was to evaluate the genotype-phenotype correlation of MYH11 from a distinctive perspective based on a pair of monozygotic twins. METHODS: The detailed phenotypic characteristics of the monozygotic twins from the early fetal stage to the infancy stage were traced and compared with each other and with those of previously documented cases. Whole-exome and Sanger sequencing techniques were used to identify and validate the candidate variants, facilitating the analysis of the genotype-phenotype correlation of MYH11. RESULTS: The monozygotic twins were premature and presented with PDA, pulmonary hypoplasia, and pulmonary hypertension. The proband developed heart and brain abnormalities during the fetal stage and died at 18 days after birth, whereas his sibling was discharged after being cured and developed normally post follow-up. A novel variant c.766 A > G p. (Ile256Val) in MYH11 (NM_002474.2) was identified in the monozygotic twins and classified as a likely pathogenic variant according to the American College of Medical Genetics/Association for Molecular Pathology guidelines. Reviewing the reported cases (n = 102) showed that the penetrance of MYH11 was 82.35%, and the most common feature was TAAD (41.18%), followed by PDA (22.55%), compound TAAD and PDA (9.80%), and other vascular abnormalities (8.82%). The constituent ratios of null variants among the cases with TAAD (8.60%), PDA (43.8%), or compound TAAD and PDA (28.6%) were significantly different (P = 0.01). Further pairwise comparison of the ratios among these groups showed that there were significant differences between the TAAD and PDA groups (P = 0.006). CONCLUSION: This study expands the mutational spectrum of MYH11 and provides new insights into the genotype-phenotype correlation of MYH11 based on the monozygotic twins with variable clinical features and outcomes, indicating that cryptic modifiers and complex mechanisms beside the genetic variants may be involved in the condition.

[Diagnosis and treatment of feline persistent ductus arteriosus: a retrospective evaluation of 17 cats]. / Diagnose und Therapie eines persistierenden Ductus arteriosus: Eine retrospektive Evaluation bei 17 Katzen.

OBJECTIVE: The objective of this study was to evaluate the signalement, clinical features, and echocardiographic findings of cats diagnosed with patent ductus arteriosus (PDA) as well as short- and medium-term outcome after successful ligation of the PDA. MATERIAL AND METHODS: Over a 10-year period 17 cats were diagnosed with PDA by transthoracic echocardiography. Thirteen cats were surgically treated by thoracotomy and ligation of the PDA. RESULTS: In all cats, a heart murmur was detected. In 88.2% of the cases, this presented as grade 4 out of 6 murmur (15/17 cats). A continuous murmur was more common (10/17 cats; 58.9%) than a systolic murmur (7/17 cats; 41.1%). Echocardiography showed that left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end systole (LVIDs) were significantly above reference values in the majority of cats. Mean diameter of the PDA measured at the widest point of the vessel was 3.4 mm (± 1.08 mm) and mean maximum flow velocity amounted to 5,06 m/sec (2,6m/sec-6,4m/sec). Surgery was successfully performed in all cats treated by surgical ligation and all of these patients were discharged after postoperative inpatient therapy. One cat experienced perioperative bleeding from the PDA, which was stopped efficaciously. This cat exhibited a residual shunt directly postoperatively; this could no longer be visualized in a re-check echocardiography 3 months later. Six cats were followed over a longer period of time. CONCLUSIONS: The surgical prognosis in this case study is very good with a postoperative survival rate of 100%. CLINICAL RELEVANCE: Surgical treatment of PDA is curative in animals not displaying advanced cardiac lesions. The auscultation of a heart murmur can provide initial findings indicative of PDA. Therefore, cardiac auscultation is warranted at every first presentation of a kitten. It must however be taken into consideration that not every cat with PDA necessarily has a continuous murmur but may display a systolic heart murmur. Therefore, it is important give utmost attention to the patients' clinical signs.

Patent ductus arteriosus management in very-low-birth-weight prematurity: a place for an early operation?

OBJECTIVES: The goal was to evaluate neonatal outcomes based on treatment strategies and time points for haemodynamically significant patent ductus arteriosus (hsPDA) in very-low-birth-weight preterm infants, with a particular focus on surgical closure. METHODS: This retrospective study included very-low-birth-weight infants born between 2014 and 2021 who received active treatment for hsPDA. Neonatal outcomes were compared between (i) primary surgical closure versus primary ibuprofen; (ii) early (<14th post-natal day) versus late primary surgical closure (≥14th post-natal day); and (iii) primary versus secondary surgical closure after ibuprofen failure. Further analysis using 1:1 propensity score matching was performed. Logistic regression was conducted to analyse the risk factors for post-ligation cardiac syndrome (PLCS) and/or acute kidney injury (AKI). RESULTS: A total of 145 infants with hsPDA underwent active treatment for closure. The in-hospital death rate and the incidence of severe bronchopulmonary dysplasia (BPD) were similar between the primary surgical closure group and the primary ibuprofen group in a 1:1 matched analysis. Severe BPD was significantly higher in the late surgical closure group than in the early primary surgical closure group with 1:1 propensity score matching (72.7% vs 40.9%, P=0.033). The secondary surgical closure group showed the mildest clinical condition; however, the probability of PLCS/AKI was highest (38.6%) compared to the early (15.2%) or the late primary surgical group (28.1%, P<0.001), especially in extremely premature infants (gestational age < 28 weeks). CONCLUSIONS: Surgical patent ductus arteriosus closure is not inferior to pharmacologic treatment. Considering the harmful effect of a prolonged patent ductus arteriosus shunt exposure, a timely decision and timely efforts should be made to minimize the risk of severe BPD and PLCS/AKI after surgical closure.

Massive left pulmonary artery aneurysm with a co-existing patent ductus arteriosus in a five-year-old female child: A case report.

Pulmonary Artery Aneur ysm (PAA), whether congenital or acquired, is a rare diagnostic find ing com pare d to aor tic aneur ysms. There have been fe w cases where PA As were documented as a complication of untreated Patent Ductus Ar teriosus (PDA) due to long-standing Pulmonary Arterial H ypertension (PAH). However, it is quite rare for a case of PAA to be reported with co-existing PDA without PAH. This report highlights a case of a five -year-old girl who was presented with palpitations, easy fatigability, fever, c yanos is, and vomiting. A Chest X-ray s howed mo derate cardiomega ly. A PDA of 6 mm was diagnosed on Transthoracic E chocardiog rap hy ( TTE ) and a large cavity con necte d with LPA raised suspicion of a possible LPA aneur ysm. A Chest CT scan confirm ed the diagnosis of a saccular aneurysm, originating from the distal part of the main Left Pulmonary Artery (LPA) just proximal to the point of bifurcation into lobar branches, measuring 7.5x6.5 cm. During surgery, the aneurysm was opened, emptied with suction and closed without resecting the aneur ysmal walls. The patient had an uneventful post-op course and is doing well during regular interval follow up visits.

Risk factors for severe bronchopulmonary dysplasia in a Chinese cohort of very preterm infants.

OBJECTIVES: To examine the risk factors for severe bronchopulmonary dysplasia (BPD) in a cohort of very preterm infants (VPIs) in China, as BPD is common among VPIs and associated with a high mortality rate. METHODS: In this multicenter retrospective study, medical records from infants with BPD born at gestation age (GA) of <32 weeks with birth weight (BW) of <1,500 grams (g) in 7 regions of China were included. The cohort was stratified into different BPD severity groups based on their fraction of inspired oxygen requirement at a modified GA of 36 weeks or post discharge. Risk factors were identified using logistic regression analysis. RESULTS: A significant inverse correlation was revealed between BPD severity and both GA and BW (p<0.001). Independent risk factors for severe BPD (sBPD) were identified as invasive mechanical ventilation (≥7d), multiple blood transfusion (≥3), nosocomial infection (NI), hemodynamically significant patent ductus arteriosus (hsPDA), delayed initiation of enteral nutrition, and longer time to achieve total caloric intake of 110 kcal/kg. Conversely, administration of antenatal steroids was associated with reduced risk of sBPD. CONCLUSION: Our study not only reaffirmed the established risk factors of low GA and BW for sBPD in VPIs, but also identified additional, potentially modifiable risk factors. Further research is warranted to explore whether intervention in these modifiable factors might reduce the risk of sBPD.Clinical Trial Reg. No.: ChiCTR1900023418.

Mobile bedside ductus arteriosus closure in severely premature neonates using only echocardiographic guidance.

BACKGROUND: Transcatheter closure of the patent ductus arteriosus (PDA) in premature infants is currently dependent on fluoroscopic guidance and transportation to the catheterization laboratory. AIM: We describe a new echocardiographically guided technique to allow our team to move to the bedside at the neonatal intensive care unit (NICU) of the referring center for percutaneous treatment of PDA in premature infants. METHODS: This is a single-center, retrospective, primarily descriptive analysis. Clinical details about the procedure, its outcomes, and complications were collected. RESULTS: Fifty-eight neonates with a median weight of 1110 g (range 730-2800) and postnatal age of 28 days (range 9-95) underwent percutaneous PDA closure. Five of them were treated in our center with ultrasound guidance only and the other 53 in 18 different neonatology units in 12 towns. The median duration of the procedure was 40 min (range 20-195 min). There were no procedural deaths. There was one residual shunt for 3 weeks, in all other patients the duct closed completely in the first few hours after the intervention. In one patient the procedure had to be interrupted because of a pericardial effusion which had to be drained, the PDA was closed successfully interventionally 5 days later. One device-related aortic coarctation had to be stented. One embolization and one late migration occurred and required treatment. CONCLUSIONS: Echocardiographically guided transcatheter closure of the PDA in prematures was repeatedly possible and allowed that the procedure is performed at the bedside at the NICU with an acceptable rate of complications.

Comparison of neurally adjusted ventilatory assist and synchronized intermittent mandatory ventilation in preterm infants after patent ductus arteriosus ligation: a retrospective study.

OBJECTIVE: This study aimed to compare the efficacy of neurally adjusted ventilatory assist (NAVA) to synchronized intermittent mandatory ventilation (SIMV) in preterm infants requiring mechanical ventilation after patent ductus arteriosus (PDA) ligation. METHODS: A retrospective analysis was conducted on intubated preterm infants who underwent PDA ligation at our hospital from July 2021 to January 2023. Infants were divided into NAVA or SIMV groups based on the ventilation mode after surgery. RESULTS: Fifty preterm infants were included. During treatment, peak inspiratory pressure (PIP) and mean airway pressure (MAP) were lower with NAVA compared to SIMV (PIP: 19.1 ± 2.9 vs. 22.4 ± 3.6 cmH2O, P < 0.001; MAP: 9.1 ± 1.8 vs. 10.9 ± 2.7 cmH2O, P = 0.002). PaO2 and PaO2/FiO2 were higher with NAVA (PaO2: 94.0 ± 11.7 vs. 84.8 ± 15.8 mmHg, P = 0.031; PaO2/FiO2: 267 [220-322] vs. 232 [186-290] mmHg, P = 0.025). Less sedation was required with NAVA (midazolam: 1.5 ± 0.5 vs. 1.1 ± 0.3 µg/kg/min, P < 0.001). CONCLUSION: Compared to SIMV, early use of NAVA post PDA ligation in preterm infants was associated with decreased PIP and MAP. Early NAVA was also associated with reduced sedation needs and improved oxygenation. However, further studies are warranted to quantify the benefits of NAVA ventilation.

Impact of catheterized ductal closure on renal and cerebral oximetry in premature neonates.

Percutaneous catheter-based closure is increasingly utilized in premature newborns. While near-infrared spectroscopy (NIRS) has been examined for assessment of interventional closure in surgical ligation, its application in percutaneous transcatheter closure remains unexplored. This study aims to assess cerebral and renal hemodynamic changes using NIRS during percutaneous closure compared to surgical closure in preterm infants. A prospective observational study enrolled preterm infants born at 32 weeks of gestation or less and diagnosed with hsPDA between January 2020 and December 2022. These infants received either surgical or catheter-based closure of the PDA. Cerebral and renal oxygen saturation was monitored using the INVOS 5100 device from 12 h before the intervention until 24 h after. Linear mixed-effects models were used to analyze time-dependent variables. Twenty-two patients were enrolled, with catheter-based closure performed in 16 cases and conventional surgery in 6 cases. Following ductal closure, a significant increase in renal and cerebral oximetry was observed alongside a decrease in renal and cerebral tissue oxygen extraction. These changes were particularly pronounced in the renal territory. No differences were detected between catheterization and surgical closure.   Conclusion: An improvement in cerebral and renal oximetry following hsPDA closure was observed. However, we did not identify differences in this pattern based on the type of interventional procedure for PDA, whether surgery or catheterization. What is Known: • The presence of a significant ductus is common in premature patients. Studies have shown that it affects cerebral and renal hemodynamics negatively, leading to decreased oximetry values in these areas. It has been reported that closure of the ductus, either pharmacologically or surgically, results in improved oximetry values. What is New: • This study assess the impact of percutaneous closure of ductus, revealing increased oximetry values in cerebral and renal territories without significant differences compared to surgical ligation. Notably, renal oximetry values showed a greater increase, underscoring the importance of multi-location monitoring.

[Risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus]. / æœ‰è¡€æµåŠ¨åŠ›å­¦æ„ä¹‰çš„åŠ¨è„‰å¯¼ç®¡æœªé—­æ—©äº§å„¿å¸ƒæ´›èŠ¬æ²»ç–—å¤±è´¥çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To investigate the risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA). METHODS: A retrospective collection of clinical data was conducted on preterm infants with a gestational age of <34 weeks who were diagnosed with hsPDA and treated at the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, from January 2018 to June 2023. The subjects were divided into two groups based on the treatment approach: the ibuprofen group (95 cases) and the ibuprofen plus surgery group (44 cases). The risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA were identified by binary logistic regression analysis. RESULTS: The binary logistic regression analysis revealed that an increased diameter of the ductus arteriosus, a resistance index (RI) value of the middle cerebral artery ≥0.80, and prolonged total invasive mechanical ventilation time were risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). Receiver operating characteristic curve analysis showed that a ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days had significant predictive value for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). The combined predictive value of these three factors was the highest, with an area under the curve of 0.843, a sensitivity of 86.5%, and a specificity of 75.0% (P<0.05). CONCLUSIONS: A ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days are risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA, and they are of significant predictive value for the necessity of surgical treatment following the failure of ibuprofen treatment.

Is Takotsubo syndrome induced by patent ductus arteriosus occlusion?

Takotsubo syndrome (TTS), commonly referred to as "broken heart syndrome," is a distinctive form of acute and reversible heart failure that primarily affects young to middle-aged individuals, particularly women. While emotional or physical stressors often trigger TTS, rare cases have been linked to interventional procedures for congenital heart disease (CHD). Despite its recognition, the exact causes of TTS remain elusive. Research indicates that dysregulation in autonomic nerve function, involving sympathetic and parasympathetic activities, plays a pivotal role. Genetic factors, hormonal influences like estrogen, and inflammatory processes also contribute, unveiling potential gender-specific differences in its occurrence. Understanding these multifaceted aspects of TTS is crucial for refining clinical approaches and therapies. Continued research efforts will not only deepen our understanding of this syndrome but also pave the way for more targeted and effective diagnostic and treatment strategies. In this report, we conduct an in-depth analysis of a case involving a TTS patient, examining the illness progression and treatment procedures. The aim of this analysis is to enhance the understanding of TTS among primary care physicians. By delving into this case, we aspire to prevent misdiagnosis of typical TTS cases that patients may present, thereby ensuring a more accurate diagnosis and appropriate treatment.

Air Transportation Impact on a Late Preterm Neonate.

BACKGROUND: Neonatal air transportation is a crucial means of moving critically ill or sick neonates to specialized neonatal intensive care units or medical centers for consultation, regardless of distance or geographical limits. Proper preparation and consideration of air transport can help alleviate medical emergencies and ensure safe delivery. However, crewmembers and neonates may face stress during transportation. To date, there are few studies on neonatal air transportation in Taiwan.CASE REPORT: We present the case of a late preterm neonate born with neonatal respiratory distress syndrome and polycythemia, who was also diagnosed with patent ductus arteriosus and mild pulmonary arterial hypertension on echocardiography. Due to disease progression, the neonate underwent endotracheal intubation and was subsequently transported to a medical center in Taiwan via a rotary-wing aircraft at 3 d of age. During takeoff and landing, a temporary oxygen desaturation event occurred. The physiological changes in these patients have seldom been discussed. This case emphasizes the important considerations of neonatal transport in Taiwan.DISCUSSION: The air transport process could be influenced by both the patient's medical condition and environmental factors. In preterm infants with cardiopulmonary conditions, thorough assessment is necessary for ensuring safe transportation.Li S-P, Hsu P-C, Huang C-Y, Wu P-W, Fang H-H. Air transportation impact on a late preterm neonate. Aerosp Med Hum Perform. 2024; 95(4):219-222.

Active versus restrictive ligation strategy for patent ductus arteriosus - A retrospective two-center study of extremely preterm infants born between 22 + 0 and 25 + 6 weeks of gestational age.

BACKGROUND: Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited in the most extremely premature infants <26 weeks of gestational age (GA), where clinical problems are most significant and patients are most vulnerable. AIMS: To investigate whether different approaches to surgical closure of PDA in two large Swedish centers has an impact on clinical outcomes including mortality in extremely preterm infants born <26 weeks GA. STUDY DESIGN: Retrospective, two-center, cohort study. SUBJECTS: Infants born at 22+0-25+6 weeks GA between 2010 and 2016 at Uppsala University Children's Hospital (UUCH; n = 228) and Queen Silvia Children's Hospital Gothenburg (QSCHG; n = 220). MAIN OUTCOME MEASURES: Survival, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP). RESULTS: Surgical closure of PDA was more common and performed earlier at QSCHG (50 % vs 16 %; median age 11 vs 44 days; p < 0.01). Survival was similar in both centres. There was a higher incidence of severe BPD and longer duration of mechanical ventilation at UUCH (p < 0.01). There was a higher incidence of ROP, IVH and sepsis at QSCH (p < 0.05, p < 0.01 and p < 0.01). A sub-group analysis matching all surgically treated infants at QSCHG with infants at UUCH with the same GA showed similar results as the total cohort. CONCLUSION: Earlier and higher rate of surgical PDA closure in this cohort of extremely preterms born <26 weeks GA did not impact mortality but was associated with lower rates of severe BPD and higher rates of severe ROP.

Analysis of perinatal risk factors for massive pulmonary hemorrhage in very low birth weight infant: A nationwide large cohort database.

OBJECTIVE: To determine perinatal risk factors for Massive pulmonary hemorrhage (MPH) and MPH-caused mortality to guide clinicians in implementing preventive measures at the beginning of life for improving the survival of very low birth weight infant (VLBWIs). STUDY DESIGN: A total of 13,826 VLBWIs born between 2013 and 2020 in the Korean Neonatal Network database were included. RESULTS: MPH occurred in 870 (6.3 %) VLBWIs. Among infants with MPH, 162 (18.6 %) VLBWIs died due to MPH. In the multivariate logistic regression analysis, independent risk factors for MPH were identified as small for gestational age, multiple gestation, high CRIB-II score, use of surfactant, and symptomatic patent ductus arteriosus (sPDA) in VLBIWs. Independent risk factors for MPH-caused mortality were identified as multiple gestation in VLBWIs. Receiving a complete course of antenatal corticosteroids (ACS) was found to be a significant independent protective factor for MPH-caused mortality in VLBWIs. CONCLUSION: Proactive managements for reducing unnecessary use of pulmonary surfactant and for decreasing the risk of sPDA at the beginning of life could be recommended as preventive strategies to reduce the risk of MPH in extremely preterm infants. ACS therapy is highly recommended for women with a high likelihood of giving birth preterm to reduce the risk of mortality caused by MPH.