Angiogenic and Inflammatory Markers of Cardiopulmonary Changes in Children and Adolescents with Sickle Cell Disease

Background: Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well. Design and Methods: Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor-BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined. Results: Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P≤0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi. Conclusions: Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated

Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: The PUSH study

In the US, mortality in sickle cell disease (SCD) increases after age 18- 20- years. Biomarkers of mortality risk can identify patients who need intensive follow- up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3- 20- years into an observational study in 2006- 2010 and followed 497 patients for a median of 88- months (range 1- 105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18- years was 99% and to 25- years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV - ¥2.7 m/second (>2 SD above the mean in age- matched and gender- matched non- SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P =- .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin - ¥2000- μg/L (observed in 60% of patients who died vs 7.8% of survivors, P <- .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P <- .001), and neutrophil count - ¥10x109/L (30.0% of patients who died vs 7.9% of survivors, P =- .018). In SCD children, adolescents and young adults, steady- state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155951/1/ajh25799_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155951/2/ajh25799.pd

Diagnosis, Prevention, Treatment and Surveillance of Anthracycline-Induced Cardiovascular Toxicity in Pediatric Cancer Survivors

Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates are some of the most commonly used agents in pediatric oncology treatment protocols, which have a dose-dependent correlation with the development of cardiac toxicity. As we learn more about the mechanisms of toxicity, we are developing prevention strategies, including improvements in surveillance, to improve early diagnosis of heart disease. Current survivorship surveillance protocols often include screening echocardiograms to evaluate systolic function by measuring the ejection fraction or fractional shortening. However, these measurements alone are not enough to capture early myocardial changes. The use of additional imaging biomarkers, serum biomarkers, electrocardiograms, as well as cholesterol and blood pressure screening, are key to the early detection of cardiomyopathy and cardiovascular disease. Medical treatment strategies are the same as those used for heart failure from other causes, but earlier recognition and implementation can lead to improved long term outcomes

Risk Factors for Symptomatic Pericardial Effusions Posthematopoietic Stem Cell Transplant

BACKGROUND: Pericardial effusions are a known complication posthematopoietic stem cell transplant (HSCT), causing significant morbidity. We aimed to evaluate the risk factors associated with the development of high-grade effusions requiring interventions. . A retrospective chart review of all HSCT patients over a period of 7 years (2013-2019) in a single institution in the Northeastern United States is conducted. All patients who developed an effusion requiring intervention were included. Patient\u27s clinical characteristics were compared with all others transplanted during the same time period. Echocardiogram findings of the affected patients were compared to a case-control cohort of unaffected patients with similar age and diagnosis. Chi-square and paired -tests were utilized to ascertain statistical differences between the groups. RESULTS: A total of 15 patients out of 201 (7.5%) transplanted at our institution developed a moderate or large pericardial effusion requiring pericardiocentesis or a pericardial window. Of this cohort, 13 (87%) underwent a myeloablative preparative regimen, 13 (87%) had cyclophosphamide as part of their regimen, 13 (87%) had recent treatment for viral reactivation, 6 (40%) had an underlying hemoglobinopathy diagnosis, and only 4 (27%) had an active diagnosis of GVHD. A myeloablative preparative regimen had a higher rate of effusion requiring intervention, although it was not statistically significant, and concurrent GVHD was not predictive of effusion development. However, exposure to cyclophosphamide, recent treatment for viral reactivation, and a diagnosis of transplant-associated thrombotic microangiopathy (Ta-TMA) were highly associated with effusions. The latter was associated with increased mortality. The duration of pericardial effusion correlated with the pretransplant echocardiogram left ventricle end diastolic diameter z-score and apical 4-chamber left ventricular peak average strain measurement. CONCLUSIONS: Potential risk factors for pericardial effusions post-HSCT include a diagnosis of Ta-TMA, active viral infection, exposure to cyclophosphamide, and a higher left ventricle end diastolic diameter -score. This information may help guide management for these patients, including identifying high-risk subjects, determining the frequency of echocardiograms, and determining specific echocardiogram measures to follow over time

Strain Echocardiography and Myocardial Dysfunction in Critically Ill Children With Multisystem Inflammatory Syndrome Unrecognized by Conventional Echocardiography: A Retrospective Cohort Analysis

OBJECTIVES: Multisystem inflammatory syndrome in children is a newly defined complication of severe acute respiratory syndrome coronavirus 2 infection that can result in cardiogenic shock in the pediatric population. Early detection of cardiac dysfunction is imperative in directing therapy and identifying patients at highest risk for deterioration. This study compares the strengths of conventional and strain echocardiography in identifying cardiac dysfunction in critically ill children with multisystem inflammatory syndrome in children and their association with ICU therapeutic needs and clinical outcomes. DESIGN: Retrospective, observational cohort study. SETTING: A large, quaternary care PICU. PATIENTS: Sixty-five pediatric patients admitted to the PICU with the diagnosis of multisystem inflammatory syndrome in children from March 2020 to March 2021. INTERVENTIONS: Global longitudinal strain four chamber was measured retrospectively by strain echocardiography and compared with conventional echocardiography. Cardiac dysfunction was defined by left ventricular ejection fraction less than 55% and global longitudinal strain four chamber greater than or equal to -17.2%. Clinical variables examined included cardiac biomarkers, immune therapies, and ICU interventions and outcomes. MEASUREMENTS AND MAIN RESULTS: Twenty-four patients (37%) had abnormal left ventricular ejection fraction and 56 (86%) had abnormal global longitudinal strain four chamber. Between patients with normal and abnormal left ventricular ejection fraction, we failed to identify a difference in cardiac biomarker levels, vasoactive use, respiratory support needs, or ICU length of stay. Global longitudinal strain four chamber was associated with maximum cardiac biomarker levels. Abnormal global longitudinal strain four chamber was associated with greater odds of any vasoactive use (odds ratio, 5.8; 95% CI, 1.3-25.3; z-statistic, 2.3; p = 0.021). The number of days of vasoactive infusion was correlated with global longitudinal strain four chamber (r = 0.400; 95% CI, 2.4-3.9; p \u3c 0.001). Children with abnormal strain had longer ICU length of stay (4.5 d vs 2 d; p = 0.014). CONCLUSIONS: Our findings suggest strain echocardiography can detect abnormalities in cardiac function in multisystem inflammatory syndrome in children patients unrecognized by conventional echocardiography. These abnormalities are associated with increased use of intensive care therapies. Evaluation of these patients with strain echocardiography may better identify those with myocardial dysfunction and need for more intensive therapy

Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease

Objectives We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD ( PUSH ) study. Methods Patients with hemoglobin SS ( n  = 376) and other sickle cell genotypes ( n  = 127) aged 3–20 yrs were studied at four centers in a cross‐sectional manner. A subgroup ( n  = 293) was followed for a median of 21 months (range 9–35). Results A patient‐reported history of one or more acute pulmonary events, either acute chest syndrome ( ACS ) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient‐reported history of asthma ( P  3 severe pain episodes in the preceding 12 months ( P  = 0.002), higher tricuspid regurgitation velocity ( TRV ) ( P  = 0.028), and higher white blood cell ( WBC ) count ( P  = 0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes ( P  = 0.009) among patients with other genotypes. During follow‐up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.0; P  < 0.0001) and younger age (odds ratio 0.9; P  = 0.007) were independently associated with developing a new episode during follow‐up. Conclusions Asthma history, frequent pain, and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98784/1/ejh12118.pd