The myocardial and coronary histopathology and pathogenesis of hypoplastic left heart syndrome

AbstractHypoplastic left heart syndrome has the greatest mortality rate among all CHDs and without palliation is uniformly fatal. Despite noble efforts, the aetiology of this syndrome is unknown and a cure remains elusive. The genetic and anatomic heterogeneity of hypoplastic left heart syndrome supports a rethinking of old hypotheses and warrants further investigation into the histological and vascular variations recognised with this syndrome. In an effort to elucidate the pathogenesis of hypoplastic left heart syndrome, this review will focus on its unique myocardial and coronary pathology as well as evaluate the association of hypoplastic left heart syndrome with the endocardial fibroelastosis reaction.</jats:p

Methylprednisolone for heart surgery in infants - A randomized, controlled trial

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown. METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (\u3c1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes. RESULTS: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P\u3c0.001). CONCLUSIONS: Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.)

3D Printing Provides a Precise Approach in the Treatment of Tetralogy of Fallot, Pulmonary Atresia with Major Aortopulmonary Collateral Arteries.

Patients with tetralogy of Fallot, pulmonary atresia, and multiple aortopulmonary collateral arteries (Tet PA MAPCAs) have a wide spectrum of anatomy and disease severity. Management of these patients can be challenging and often require multiple high-risk surgical and interventional catheterization procedures. These interventions are made challenging by complex anatomy that require the proceduralist to mentally reconstruct three-dimensional anatomic relationships from two-dimensional images. Three-dimensional (3D) printing is an emerging medical technology that provides added benefits in the management of patients with Tet PA MAPCAs. When used in combination with current diagnostic modalities and procedures, 3D printing provides a precise approach to the management of these challenging, high-risk patients. Specifically, 3D printing enables detailed surgical and interventional planning prior to the procedure, which may improve procedural outcomes, decrease complications, and reduce procedure-related radiation dose and contrast load

Dynamic fluid shifts induced by fetal bypass

ObjectiveFluid shifts have been suggested to occur with fetal bypass. The degree or mechanisms behind these volume changes (or location) have not been defined. We characterized the preceding and correlated the findings to plasma vasopressin concentrations, the critical peptide of osmoregulation.MethodsSeventeen ovine fetuses (105–111 days' gestation) were started on bypass and followed 2 hours after bypass. Hemodynamics and volume replacements needed to maintain minimum reservoir volume during bypass and normal physiologic parameters after bypass were recorded. Serial blood samples were collected to assess gas exchange and vasopressin levels. Changes in total tissue water content were measured for several organs and the placenta. Plasma volume, fluid shifts, and osmolarity were calculated.ResultsHematocrit values decreased by 15 minutes of bypass to 28% from 33% and then increased to 34% by 120 minutes after bypass, corresponding to a decreased fetal plasma volume of 79 to 72 mL/kg by 120 minutes after bypass. The majority of volume shifts (approximately 100 mL/kg) occurred during bypass, but additional volume replacements were required after bypass to maintain normal hemodynamics, resulting in overall losses of 0.8 mL · kg−1 · min−1. Losses were not accounted for by placental or organ edema. Vasopressin levels increased dramatically with bypass (39–51.5 pg/mL) and were strongly predicted by increased fetal plasma volumes (R2 = 0.90), whereas osmolarity was not significantly associated with plasma volumes.ConclusionFetal bypass leads to significant fluid shifts that correlate strongly with increasing vasopressin levels (but not changes in osmolarity). The placenta is not the primary site of volume loss. Rehydration of the fetus is necessary after bypass

Coxsackievirus B3 infection early in pregnancy induces congenital heart defects through suppression of fetal cardiomyocyte proliferation

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-β1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes

Infectious Complications of Ventricular Assist Device Use in Children in the US: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs)

Background Infections are frequent in pediatric ventricular assist device (VAD) patients. In this study we aimed to describe infections in durable VAD patients reported to Pedimacs. Methods Durable VAD data from the Pedimacs registry (September 19, 2012 to December 31, 2015) were analyzed. Infections were described with standard descriptive statistics, Kaplan–Meier analysis and competing outcomes analysis. Results There were 248 implants in 222 patients, with a mean age and a median follow-up of 11 ± 6.4 years and 2.4 patient-months (<1 day to 2.6 years), respectively. Device types were pulsatile flow (PF) in 91 (41%) patients and continuous flow (CF) in 131 (59%) patients. PF patients were younger (4 ± 4 vs 14 ± 4 years; p < 0.0001) and were more likely to have congenital heart disease (25% vs 12%; p = 0.03), prior surgery (53% vs 26%; p < 0.0001) and prior extracorporeal membrane oxygenation (24% vs 7%; p = 0.0003). Infection accounted for 17% (96 of 564) of the reported adverse events (AEs). A non-device infection was most common (51%), followed by sepsis (24%), external pump component infection (20%) and internal pump component infection (5%). Most infections were bacterial (73%) and required intravenous therapy only (77%). The risk of infection in the constant phase was higher in patients with a history of prior infection and in patients with a history of a non-infectious major AEs. Survival was lower after infection only in CF patients (p = 0.008). Conclusions Infection was the most common AE after pediatric VAD implantation. Non-device infections were most common. The best predictor of a future infection was a past infection. CF patients have higher risk of death after an infection

A case of persistent human pegivirus infection in two separate pregnancies of a woman

Human pegivirus (HPgV) is best known for persistent, presumably non-pathogenic, infection and a propensity to co-infect with human immunodeficiency virus or hepatitis C virus. However, unique attributes, such as the increased risk of malignancy or immune modulation, have been recently recognized for HPgV. We have identified a unique case of a woman with high levels HPgV infection in two pregnancies, which occurred 4 years apart and without evidence of human immunodeficiency virus or hepatitis C virus infection. The second pregnancy was complicated by congenital heart disease. A high level of HPgV infection was detected in the maternal blood from different trimesters by RT-PCR and identified as HPgV type 1 genotype 2 in both pregnancies. In the second pregnancy, the decidua and intervillous tissue of the placenta were positive for HPgV by PCR but not the chorion or cord blood (from both pregnancies), suggesting no vertical transmission despite high levels of viremia. The HPgV genome sequence was remarkably conserved over the 4 years. Using VirScan, sera antibodies for HPgV were detected in the first trimester of both pregnancies. We observed the same anti-HPgV antibodies against the non-structural NS5 protein in both pregnancies, suggesting a similar non-E2 protein humoral immune response over time. To the best of our knowledge, this is the first report of persistent HPgV infection involving placental tissues with no clear indication of vertical transmission. Our results reveal a more elaborate viral-host interaction than previously reported, expand our knowledge about tropism, and opens avenues for exploring the replication sites of this virus

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure