ASE Statement on Adapting Pediatric, Fetal, and Congenital Heart Disease Echocardiographic Services to the Evolving COVID-19 Pandemic.

Over the 12 months since the start of the coronavirus disease 2019 pandemic, an explosion of investigation and an increase in experience have led to vast improvement in our knowledge about this disease. However, coronavirus disease 2019 remains a huge public health threat.

Not just vegetations: focal myocardial changes in patients with fungal infections.

BACKGROUND: Fungal endocarditis classically involves dense heterogenous vegetations. However, several patients with fungal infections were noted to have myocardial changes ranging from focal brightening to nodular thickening of chordae or papillary muscles. This study evaluates whether these findings are associated with fungal infections. METHODS: In a retrospective case-control study, paediatric inpatients with fungal infections (positive blood, urine, or catheter tip culture) in a 5-year period were matched 1:1 to inpatients without positive fungal cultures. Echocardiograms were scored on a 5-point scale by two independent readers for presence of myocardial brightenings, nodular thickenings, and vegetations. Clinical data were compared. RESULTS: Of 67 fungal cases, positive culture sites included blood (n = 44), vascular catheter tip (n = 7), and urine (n = 29); several had multiple positive sites. "Positive" echo findings (score ≥ 2+) were more frequent in the Fungal Group (33 versus 18%, p = 0.04). Fungal Group patients with "positive" versus "negative" echo findings had similar proportion of bacterial infections. Among fungal cases, those with "positive" echo findings had longer hospital length of stay than cases with "negative" echos (median 58 versus 40 days, p = 0.03) but no difference in intensive care unit admission, extracorporeal membranous oxygenation support, or mortality. CONCLUSIONS: Myocardial and papillary muscle brightening with nodular thickening on echocardiogram appear to be associated with fungal infections. There may be prognostic implications of these findings as patients with "positive" echo have longer length of stay. Further studies are needed to better understand the mechanism and temporal progression of these changes and determine the prognostic value of this scoring system.

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.

Temporal relationship between instantaneous pressure gradients and peak-to-peak systolic ejection gradient in congenital aortic stenosis.

OBJECTIVE: We sought to identify a time during cardiac ejection when the instantaneous pressure gradient (IPG) correlated best, and near unity, with peak-to-peak systolic ejection gradient (PPSG) in patients with congenital aortic stenosis. Noninvasive echocardiographic measurement of IPG has limited correlation with cardiac catheterization measured PPSG across the spectrum of disease severity of congenital aortic stenosis. A major contributor is the observation that these measures are inherently different with a variable relationship dependent on the degree of stenosis. DESIGN: Hemodynamic data from cardiac catheterizations utilizing simultaneous pressure measurements from the left ventricle (LV) and ascending aorta (AAo) in patients with congenital valvar aortic stenosis was retrospectively reviewed over the past 5 years. The cardiac cycle was standardized for all patients using the percentage of total LV ejection time (ET). Instantaneous gradient at 5% intervals of ET were compared to PPSG using linear regression and Bland-Altman analysis. RESULTS: A total of 22 patients underwent catheterization at a median age of 13.7 years (interquartile range [IQR] 10.3-18.0) and median weight of 51.1 kg (IQR 34.2-71.6). The PPSG was 46.5 ± 12.6 mm Hg (mean ± SD) and correlated suboptimally with the maximum and mean IPG. The midsystolic IPG (occurring at 50% of ET) had the strongest correlation with the PPSG ( PPSG = 0.97(IPG50%)-1.12, R2 = 0.88), while the IPG at 55% of ET was closest to unity ( PPSG = 0.997(IPG55%)-1.17, R2 = 0.87). CONCLUSIONS: The commonly measured maximum and mean IPG are suboptimal estimates of the PPSG in congenital aortic stenosis. Using catheter-based data, IPG at 50%-55% of ejection correlates well with PPSG. This may allow for a more accurate estimation of PPSG via noninvasive assessment of IPG.

Handheld echocardiography versus auscultation for detection of rheumatic heart disease.

BACKGROUND: Rheumatic heart disease (RHD) remains a major public health concern in developing countries, and routine screening has the potential to improve outcomes. Standard portable echocardiography (STAND) is far more sensitive than auscultation for the detection of RHD but remains cost-prohibitive in resource-limited settings. Handheld echocardiography (HAND) is a lower-cost alternative. The purpose of this study was to assess the incremental value of HAND over auscultation to identify RHD. METHODS: RHD screening was completed for schoolchildren in Gulu, Uganda, by using STAND performed by experienced echocardiographers. Any child with mitral or aortic regurgitation or stenosis plus a randomly selected group of children with normal STAND findings underwent HAND and auscultation. STAND and HAND studies were interpreted by 6 experienced cardiologists using the 2012 World Heart Federation criteria. Sensitivity and specificity of HAND and auscultation for the detection of RHD and pathologic mitral or aortic regurgitation were calculated by using STAND as the gold standard. RESULTS: Of 4773 children who underwent screening with STAND, a subgroup of 1317 children underwent HAND and auscultation. Auscultation had uniformly poor sensitivity for the detection of RHD or valve disease. Sensitivity was significantly improved by using HAND compared with auscultation for the detection of definite RHD (97.8% vs 22.2%), borderline or definite RHD (78.4% vs 16.4%), and pathologic aortic insufficiency (81.8% vs 13.6%). CONCLUSIONS: Auscultation alone is a poor screening test for RHD. HAND significantly improves detection of RHD and may be a cost-effective screening strategy for RHD in resource-limited settings.

Simplified rheumatic heart disease screening criteria for handheld echocardiography.

BACKGROUND: Using 2012 World Heart Federation criteria, standard portable echocardiography (STAND) reveals a high burden of rheumatic heart disease (RHD) in resource-poor settings, but widespread screening is limited by cost and physician availability. Handheld echocardiography (HAND) may decrease costs, but World Heart Federation criteria are complicated for rapid field screening, particularly for nonphysician screeners. The aim of this study was to determine the best simplified screening strategy for RHD detection using HAND. METHODS: In this prospective study, STAND (GE Vivid q or i or Philips CX-50) was performed in five schools in Gulu, Uganda; a random subset plus all children with detectable mitral regurgitation or aortic insufficiency also underwent HAND (GE Vscan). Borderline or definite RHD cases were defined by 2012 World Heart Federation criteria on STAND images, by two experienced readers. HAND studies were reviewed by cardiologists blinded to STAND results. Single and combined HAND parameters were evaluated to determine the simplified screening strategy that maximized sensitivity and specificity for case detection. RESULTS: In 1,439 children (mean age, 10.8 ± 2.6 years; 47% male) with HAND and STAND studies, morphologic criteria and the presence of any mitral regurgitation by HAND had poor specificity. The presence of aortic insufficiency was specific but not sensitive. Combined criteria of mitral regurgitation jet length ≥ 1.5 cm or any aortic insufficiency best balanced sensitivity (73.3%) and specificity (82.4%), with excellent sensitivity for definite RHD (97.9%). With a prevalence of 4% and subsequent STAND screening of positive HAND studies, this would reduce STAND studies by 80% from a STAND-based screening strategy. CONCLUSIONS: In resource-limited settings, HAND with simplified criteria can detect RHD with good sensitivity and specificity and decrease the need for standard echocardiography. Further study is needed to validate screening by local practitioners and long-term outcomes.

Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia.

Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography, and lung diffusing capacity in 146 children aged 7 to 20 years with hemoglobin SS or Sß(0)-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient-reported or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower forced expiratory volume in the first second/forced vital capacity. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and Sß(0)-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or Sß(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers.

Differences in the clinical and genotypic presentation of sickle cell disease around the world.

Sickle cell disease (SCD), caused by a mutation in the ß-globin gene HBB, is widely distributed in malaria endemic regions. Cardiopulmonary complications are major causes of morbidity and mortality. Hemoglobin SS (Hb SS) represents a large proportion of SCD in the Americas, United Kingdom, and certain regions of Africa while higher proportions of hemoglobin SC are observed in Burkina Faso and hemoglobin Sß-thalassemia in Greece and India. Coinheritance of α-thalassemia and persistence of hemoglobin F production are observed in highest frequency in certain regions of India and the Middle East. As confirmed in the PUSH and Walk-PHaSST studies, Hb SS, absence of co-inheriting alpha-thalassemia, and low hemoglobin F levels tend to be associated with more hemolysis, lower hemoglobin oxygen saturations, greater proportions of elevated tricuspid regurgitant jet velocity and brain natriuretic peptide, and increased left ventricular mass index. Identification of additional genetic modifiers will improve prediction of cardiopulmonary complications in SCD.

Multicenter study comparing shunt type in the norwood procedure for single-ventricle lesions: three-dimensional echocardiographic analysis.

BACKGROUND: The Pediatric Heart Network's Single Ventricle Reconstruction (SVR) trial randomized infants with single right ventricles (RVs) undergoing a Norwood procedure to a modified Blalock-Taussig or RV-to-pulmonary artery shunt. This report compares RV parameters in the 2 groups using 3-dimensional echocardiography. METHODS AND RESULTS: Three-dimensional echocardiography studies were obtained at 10 of 15 SVR centers. Of the 549 subjects, 314 underwent 3-dimensional echocardiography studies at 1 to 4 time points (pre-Norwood, post-Norwood, pre-stage II, and 14 months) for a total of 757 3-dimensional echocardiography studies. Of these, 565 (75%) were acceptable for analysis. RV volume, mass, mass:volume ratio, ejection fraction, and severity of tricuspid regurgitation did not differ by shunt type. RV volumes and mass did not change after the Norwood, but increased from pre-Norwood to pre-stage II (end-diastolic volume [milliliters]/body surface area [BSA](1.3), end-systolic volume [milliliters]/BSA(1.3), and mass [grams]/BSA(1.3) mean difference [95% confidence interval]=25.0 [8.7-41.3], 19.3 [8.3-30.4], and 17.9 [7.3-28.5], then decreased by 14 months (end-diastolic volume/BSA(1.3), end-systolic volume/BSA(1.3), and mass/BSA(1.3) mean difference [95% confidence interval]=-24.4 [-35.0 to -13.7], -9.8 [-17.9 to -1.7], and -15.3 [-22.0 to -8.6]. Ejection fraction decreased from pre-Norwood to pre-stage II (mean difference [95% confidence interval]=-3.7 [-6.9 to -0.5]), but did not decrease further by 14 months. CONCLUSIONS: We found no statistically significant differences between study groups in 3-dimensional echocardiography measures of RV size and function, or magnitude of tricuspid regurgitation. Volume unloading was seen after stage II, as expected, but ejection fraction did not improve. This study provides insights into the remodeling of the operated univentricular RV in infancy.

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 < 0.0001), older age (P = 0.001), >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.

5/6 Area length method for left-ventricular ejection-fraction measurement in adults with repaired tetralogy of Fallot: comparison with cardiovascular magnetic resonance.

In patients with repaired tetralogy of Fallot (rTOF), left-ventricular ejection fraction (LVEF) predicts adverse outcomes. Two-dimensional echocardiographic (2DE) methods of measuring LVEF require geometric assumptions and may be limited in this population due to altered ventricular geometry. This study evaluated the performance of the 5/6 area × length (AL) method in this population as well as which factors limit agreement with the results of cardiovascular magnetic resonance (CMR). In 20 patients with rTOF (28.5 ± 14.7 years old) and CMR and 2DE within 3 months, two investigators blinded to CMR measured LVEF from 2DE by the AL method, biplane Simpson's (BiS) method, and visual estimate. Two investigators blinded to 2DE measured LVEF from CMR by Simpson's and AL methods. The AL method on 2DE more closely approximated LVEF by CMR (r = 0.73, p = 0.0003) than BiS method (r = 0.53, p = 0.02). AL method was not limited by geometric assumptions, as AL method on CMR closely approximated Simpson's method on CMR (r = 0.90, p < 0.0001) despite median left-ventricular diastolic eccentricity index of 1.24. AL method on 2DE was primarily limited by short-axis area measurement rather than foreshortening of the ventricle. In conclusion, in adults with rTOF, AL method on 2DE moderately approximates LVEF by CMR, even in the context of altered left-ventricular geometry. Although the AL method may be the most appropriate 2DE method in this population, significant limitations remain for LVEF assessment by 2DE, and strategies to optimize image position and border detection are essential.

Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia.

OBJECTIVE: To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of patients with sickle cell anemia (SCA) enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease. STUDY DESIGN: Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with those of subjects with <3 such episodes. RESULTS: Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR, 1.2; 95% CI, 1.1-1.3; P < .0001), α-thalassemia trait (OR 3.5; 1.6-6.7; P = .002), higher median hemoglobin (OR 1.7; 95% CI: 1.2-2.4; P < .003), and lower lactate dehydrogenase concentration (OR 1.82; 95% CI: 1.07-3.11; P = .027). Children with high pain frequency also had an increased iron burden (serum ferritin, 480 vs 198 µg/L; P = .006) and higher median tricuspid regurgitation jet velocity (2.41 vs 2.31 m/s; P = .001). Neither hydroxyurea use nor fetal hemoglobin levels were significantly different according to severe pain history. CONCLUSIONS: In our cohort of children with SCA, increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower lactate dehydrogenase concentration, and higher tricuspid regurgitation velocity.

Predictors of osteoclast activity in patients with sickle cell disease.

BACKGROUND: Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. DESIGN AND METHODS: We examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrate-resistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. RESULTS: Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=-0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). CONCLUSIONS: Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.

Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia.

BACKGROUND: While in adults with sickle cell disease an elevation of tricuspid regurgitation velocity is associated with increased mortality, the importance of this finding in children has not been established. The role of intravascular hemolysis in the development of this complication is controversial. DESIGN AND METHODS: We conducted a prospective, longitudinal, multi-center study of 160 individuals aged 3-20 years with hemoglobin SS, performing baseline and follow-up determinations of clinical markers, six-minute walk distance less than tricuspid regurgitation velocity and E/Etdi ratio by echocardiography. RESULTS: At baseline, 14.1% had tricuspid regurgitation velocity of 2.60 m/sec or over, which suggests elevated systolic pulmonary artery pressure, and 7.7% had increased E/Etdi, which suggests elevated left ventricular filling pressure. Over a median of 22 months, baseline elevation in tricuspid regurgitation velocity was associated with an estimated 4.4-fold increase in the odds of a 10% or more decline in age-standardized six-minute-walk distance (P = 0.015). During this interval, baseline values above the median for a hemolytic component derived from four markers of hemolysis were associated with a 9.0-fold increase in the odds of the new onset of elevated tricuspid regurgitation velocity (P = 0.008) and baseline E/Etdi elevation was associated with an estimated 6.1-fold increase in the odds (P = 0.039). In pathway analysis, higher baseline hemolytic component and E/Etdi predicted elevated tricuspid regurgitation velocity at both baseline and follow up, and these elevations in turn predicted decline in six-minute-walk distance. CONCLUSIONS: Further studies should define the long-term risks of elevated tricuspid regurgitation velocity in childhood and identify potential interventions to prevent increased pulmonary artery pressure and preserve function.