Impaired cell-cell communication and axon guidance because of pulmonary hypoperfusion during postnatal alveolar development.

BACKGROUND: Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. METHODS AND RESULTS: We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell-cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. CONCLUSIONS: This study suggested that promoting cell-cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion-induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion.

Fifty years of pediatric cardiology (1971-2021): from Fontan's surgery to the present day

Pediatric cardiology has matured profoundly over the last 50 years, paralleled by a similar development in pediatric cardiac surgery and cardiac anesthesia. This field of medicine provides structured and effective care for a very heterogeneous group of diseases including congenital heart disease, cardiomyopathies and heart failure, myocarditis, rheumatic heart disease, inherited and acquired arrhythmias, Kawasaki disease and more recently multisystemic inflammatory syndrome of children related to primary infection by SARS-CoV-2. This review summarizes achievements and results in selected topics of pediatric cardiology and cardiac surgery with focused attention to the diagnosis and management of congenital heart diseases.

Cardiovascular impact of COVID-19 with a focus on children: A systematic review.

BACKGROUND: Since the beginning of the pandemic, coronavirus disease-2019 (COVID-19) in children has shown milder cases and a better prognosis than adults. Although the respiratory tract is the primary target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cardiovascular involvement is emerging as one of the most significant and life-threatening complications of SARS-CoV-2 infection in adults. AIM: To summarize the current knowledge about the potential cardiovascular involvement in pediatric COVID-19 in order to give a perspective on how to take care of them during the current pandemic emergency. METHODS: Multiple searches in MEDLINE, PubMed were performed using the search terms "COVID-19" or "SARS-CoV-2" were used in combination with "myocardial injury" or "arrhythmia" or "cardiovascular involvement" or "heart disease" or "congenital heart disease" or "pulmonary hypertension" or "long QT" or "cardiomyopathies" or "channelopathies" or "Multisystem inflammatory system" or "PMIS" or "MIS-C" or "Pediatric multisystem inflammatory syndrome" or "myocarditis" or "thromboembolism to identify articles published in English language from January 1st, 2020 until July 31st, 2020. The websites of World Health Organization, Centers for Disease control and Prevention, and the Johns Hopkins Coronavirus Resource Center were reviewed to provide up to date numbers and infection control recommendations. Reference lists from the articles were reviewed to identify additional pertinent articles. Retrieved manuscripts concerning the subject were reviewed by the authors, and the data were extracted using a standardized collection tool. Data were subsequently analyzed with descriptive statistics. For Pediatric multisystemic inflammatory syndrome temporally associated with COVID-19 (PMIS), multiple meta-analyses were conducted to summarize the pooled mean proportion of different cardiovascular variables in this population in pseudo-cohorts of observed patients. RESULTS: A total of 193 articles were included. Most publications used in this review were single case reports, small case series, and observational small-sized studies or literature reviews. The meta-analysis of 16 studies with size > 10 patients and with complete data about cardiovascular involvement in children with PMIS showed that PMIS affects mostly previously healthy school-aged children and adolescents presenting with Kawasaki disease-like features and multiple organ failure with a focus on the heart, accounting for most cases of pediatric COVID-19 mortality. They frequently presented cardiogenic shock (53%), ECG alterations (27%), myocardial dysfunction (52%), and coronary artery dilation (15%). Most cases required PICU admission (75%) and inotropic support (57%), with the rare need for extracorporeal membrane oxygenation (4%). Almost all of these children wholly recovered in a few days, although rare deaths have been reported (2%). Out of PMIS cases we identified 10 articles reporting sporadic cases of myocarditis, pulmonary hypertension and cardiac arrythmias in previously healthy children. We also found another 10 studies reporting patients with pre-existing heart diseases. Most cases consisted in children with severe COVID-19 infection with full recovery after intensive care support, but cases of death were also identified. The management of different cardiac conditions are provided based on current guidelines and expert panel recommendations. CONCLUSION: There is still scarce data about the role of cardiovascular involvement in COVID-19 in children. Based on our review, children (previously healthy or with pre-existing heart disease) with acute COVID-19 requiring hospital admission should undergo a cardiac workup and close cardiovascular monitoring to identify and treat timely life-threatening cardiac complications.