Patients suffering from vascular disease often have impaired angiogenic ability contributing to impaired tissue repair. One potential therapy is to deliver cells that can aid in angiogenesis. This ...review will discuss the ability of endothelial progenitor cells (EPCs), which have been reported to contribute to neoangiogenesis in both physiological and pathological conditions, to contribute to neoangiogenesis in tissue repair.
In recent years, various reports have described conflicting roles for EPC in vessel formation. Currently there are three different assays for outgrowth of EPC all resulting in the isolation of different cell populations. This confusion is partially due to limited functional characterization of putative EPC populations. One population, endothelial colony-forming cell (ECFC), has been shown to possess all the characteristics of a true endothelial progenitor.
The review overviews the role of putative EPC populations in angiogenesis and tissue repair. Whereas all EPC populations have been shown to play a role in angiogenesis, only ECFC have demonstrated the ability to form de-novo blood vessels in vivo. Additionally ECFC have been shown to play a role in neovascularization in several preclinical rodent models suggesting that it may be an excellent cell source for treatment of patients with diminished vascular function.
Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are ...technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.
We hypothesized that neonatal cardiac magnetic resonance imaging (MRI) will correlate with BPD severity and predict short-term clinical outcomes, including need for PH therapies for infants with BPD.
A total of 52 infants (31 severe BPD, 9 moderate BPD, and 12 with either mild or no BPD) were imaged between 39 and 47 weeks postmenstrual age on a neonatal-sized, neonatal ICU-sited 1.5-T magnetic resonance (MR) scanner. MR left ventricular eccentricity index (EI), main pulmonary artery-to-aorta (PA/AO) diameter ratio, and pulmonary arterial blood flow were determined. Echos obtained for clinical indications were reviewed. MRI and echo indices were compared with BPD severity and clinical outcomes, including length of stay (LOS), duration of respiratory support, respiratory support at discharge, and PH therapy.
PA/AO ratio increased with BPD severity. Increased PA/AO ratio, MR-EI, and echo-EIs were associated with increased LOS and duration of respiratory support. No correlation was seen between pulmonary arterial blood flow and BPD outcomes. Controlling for gestational age, birth weight, and BPD severity, MR-EI was associated with LOS and duration of respiratory support. Increased PA/AO ratio and MR-EI were associated with PH therapy during hospitalization and at discharge.
MRI can provide important image-based measures of cardiac morphology that relate to disease severity and clinical outcomes in neonates with BPD.
Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of ...cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy.
Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy.
CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R
= 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI.
CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.
To evaluate the cost-utility of catheterization-obligate treatment in preterm infants with pulmonary hypertension, as compared with empiric initiation of sildenafil based on echocardiographic ...findings alone.
A Markov state transition model was constructed to simulate the clinical scenario of a preterm infant with echocardiographic evidence of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD) and without congenital heart disease under consideration for the initiation of pulmonary vasodilator therapy via one of two modeled treatment strategies—empiric or catheterization-obligate. Transitional probabilities, costs and utilities were extracted from the literature. Forecast quality-adjusted life-years was the metric for strategy effectiveness. Sensitivity analyses for each variable were performed. A 1000-patient Monte Carlo microsimulation was used to test the durability of our findings.
The catheterization-obligate strategy resulted in an increased cost of $10 778 and 0.02 fewer quality-adjusted life-years compared with the empiric treatment strategy. Empiric treatment remained the more cost-effective paradigm across all scenarios modeled through one-way sensitivity analyses and the Monte Carlo microsimulation (cost-effective in 98% of cases).
Empiric treatment with sildenafil in infants with pulmonary hypertension associated with BPD is a superior strategy with both decreased costs and increased effectiveness when compared with catheterization-obligate treatment. These findings suggest that foregoing catheterization before the initiation of sildenafil is a reasonable strategy in preterm infants with uncomplicated pulmonary hypertension associated with BPD.
Multiple right ventricular (RV) metrics have prognostic value in pulmonary hypertension (PH). A cardiac magnetic resonance imaging (CMR) derived global ventricular function index (GFI) provided ...improved prediction of composite adverse outcome (CAO) in adults with atherosclerosis. GFI has not yet been explored in a PH population. We explored the feasibility of GFI as a predictor of CAO in a pediatric PH population.
Two center retrospective chart review identified pediatric PH patients undergoing CMR from Jan 2005–June 2021. GFI, defined as the ratio of the stroke volume to the sum of mean ventricular cavity and myocardial volume, was calculated for each patient. CAO was defined as death, lung transplant, Potts shunt, or parenteral prostacyclin initiation after CMR. Cox proportional hazards regression was used to estimate associations and assess model performance between CMR parameters and CAO.
The cohort comprised 89 patients (54% female, 84% World Health Organization (WHO) Group 1; 70% WHO-FC ≤ 2; and 27% on parenteral prostacyclin). Median age at CMR was 12 years (IQR 8.1–17). Twenty-one (24%) patients experienced CAO during median follow up of 1.5 years. CAO cohort had higher indexed RV volumes (end systolic—145 vs 99 mL/m2, p = 0.003; end diastolic—89 vs 46 mL/m2, p = 0.004) and mass (37 vs 24 gm/m2, p = 0.003), but lower ejection fraction (EF) (42 vs 51%, p < 0.001) and GFI (40 vs 52%, p < 0.001). Higher indexed RV volumes (hazard ratios HR 1.01, CI 1.01–1.02), lower RV EF (HR 1.09, CI 1.05–1.12) and lower RV GFI (HR 1.09, CI 1.05–1.11) were associated with increased risk of CAO. In survival analysis, patients with RV GFI < 43% demonstrated decreased event-free survival and increased hazard of CAO compared to those with RV GFI ≥ 43%. In multivariable models, inclusion of GFI provided improved prediction of CAO compared to models incorporating ventricular volumes, mass or EF.
RV GFI was associated with CAO in this cohort, and inclusion in multivariable models had increased predictive value compared to RVEF. GFI uses readily available CMR data without additional post-processing and may provide additional prognostic value in pediatric PH patients beyond traditional CMR markers.
While advanced therapies for severe persistent pulmonary hypertension of the newborn (PPHN) such as inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) are standard treatments ...in high-income countries, these therapies are often unavailable in resource-limited settings such as middle-income countries. However, there are small clinical trials illustrating the efficacy of sildenafil at reducing mortality in PPHN. This analysis sought to determine the cost-utility of enteral sildenafil for the treatment of severe PPHN.
A Markov-state transition model was constructed for the two clinical approaches to compare costs, clinical outcomes, and quality of life: (1) "conventional," (2) "sildenafil." The impact of sildenafil was modeled as a relative risk modifier of the conventional strategy's mortality risk. Transitional probabilities, costs, and utility metrics were extracted from the literature. Sensitivity analyses for each model input as well as 100-patient Monte Carlo simulations were used to test the durability of the model conclusion.
The sildenafil strategy was cost-effective for upper but not lower middle-income countries with an incremental cost-effectiveness ratio of $2,339 per quality-adjusted life year. This conclusion was durable across a wide-range of model assumptions; the sildenafil strategy only failed to meet criteria for cost-effectiveness when sildenafil therapy had a mortality relative risk efficacy of >0.89, if life expectancy in that country is <40 years, or if the lifetime forecasted costs of a survivor's life was quite high.
Enteral sildenafil is a cost-effective intervention for severe PPHN for upper middle-income countries where ECMO and iNO are not available.
· PPHN is a common life-threatening condition in newborns.. · Sildenafil improves survival of PPHN.. · Sildenafil is cost-effective for upper-middle income countries..
To determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia repair.
This is a single-center, retrospective cohort study of CDH ...survivors who underwent exercise stress echocardiography (ESE) at Boston Children's Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure).
Eighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 – 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE.
Among long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH.
Bronchopulmonary dysplasia (BPD) is a common long-term complication of preterm birth. The chest radiograph appearance and survivability have evolved since the first description of BPD in 1967 because ...of improved ventilation and clinical strategies and the introduction of surfactant in the early 1990s. Contemporary imaging care is evolving with the recognition that comorbidities of tracheobronchomalacia and pulmonary hypertension have a great influence on outcomes and can be noninvasively evaluated with CT and MRI techniques, which provide a detailed evaluation of the lungs, trachea and to a lesser degree the heart. However, echocardiography remains the primary modality to evaluate and screen for pulmonary hypertension. This review is intended to highlight the important findings that chest radiograph, CT and MRI can contribute to precision diagnosis, phenotyping and prognosis resulting in optimal management and therapeutics.
Objective
Congenital diaphragmatic hernia (CDH) survivors are at risk for long‐term exercise impairment and pulmonary morbidity, but the generalizability of prior reported cohorts are limited by ...reduced disease severity and older surgical eras. We assessed the mid‐childhood exercise and pulmonary function outcomes in a contemporary cohort of CDH survivors.
Study Design
In this retrospective cohort study, we identified 36 consecutive pediatric CDH survivors who underwent cardiopulmonary exercise testing (CPET) and spirometry from 2014 to 2021. Inferential statistics compared survivors with age‐, sex‐, and size‐matched healthy controls; univariate analyses identified factors associated with abnormal testing.
Results
Maximal effort CPET and resting spirometry were completed by 27/36 (75%) and 31/36 (86%) subjects, respectively (median age: 8.1 years interquartile range: 7.5, 10; 16 females 44%). Abnormal CPET (percent predicted pp peak VO2 < 80%) was more common in the CDH cohort (12 vs. 1, p < 0.001) and associated with longer neonatal intensive care unit (NICU) stay (p = 0.02) and oxygen therapy at discharge (p = 0.03). Exercise impairment was mild (pp peak VO2 70%–80%), moderate (60%–70%), and severe (<60%) in 6, 4, and 2 survivors, respectively. Abnormal spirometry was more common in the CDH cohort (21 vs. 3, p < 0.001; obstructive n = 15, restrictive n = 6) and associated with decreased gestational age (p = 0.046), longer mechanical ventilation in the NICU (p = 0.02), and orthopedic abnormalities (p = 0.03).
Conclusion(s)
Exercise capacity was normal or mildly impaired in most CDH survivors, however, approximately two‐thirds demonstrated abnormal spirometry. Impaired exercise capacity and lung function were associated with severity of lung disease postnatally. These data support cardiopulmonary follow‐up throughout childhood.
Pulmonary vascular disease (PVD) represents an important clinical indication for lung transplant (LTx) in infants, children, and adolescents. There is limited information on LTx outcomes in these ...patients. We explored LTx volumes and post-LTx survival in children with PVD compared to other diagnoses. The UNOS Registry was queried from 1989 to 2020 to identify first-time pediatric LTx recipients (< 18 yo). PVD was categorized as idiopathic pulmonary arterial hypertension (IPAH) and non-idiopathic arterial hypertension (non-IPAH) and compared to all other patients as other diagnoses. Univariate and multivariate regression models were performed. 984 pediatric LTx patients (593 before 2010 and 391 during/after 2010) were identified, of which 145 (14.7%) had PVD. There has been no significant change in annual rate of all LTxs over comparative eras. However, there has been a decrease in rate of LTxs for PVD patients. Children with PVD had similar survival to other LTx groups in the early era (
p
= 0.2) and the latter era (
p
= 0.9). Univariate Cox models, showed that LTx in patients with PVD was associated with a significantly less risk of mortality for children aged 6–11 years compared to younger and older cohorts (HR = 0.4 0.17–0.98;
p
= 0.045), whereas multivariate analysis showed a trend toward higher mortality in 11–17-year-olds (HR = 1.54 0.97–2.45;
p
= 0.06). For PVD patients, oxygen supplementation and ventilator support at LTx were associated with worse post-transplant survival (
p
= 0.029 and
p
= 0.01). There has been a decrease in LTx volume for pediatric patients with PVD in the modern era. Post-LTx outcomes for children with PVD are similar to those of other diagnoses in both eras, with children aged 6–11 years having the best survival. Given these findings, LTx should be considered for this patient population.
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