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Background Blood speckle tracking echocardiography allows for direct quantification of interventricular and aortic flow profiles, principally in children. Here, we sought to demonstrate the feasibility and reproducibility of blood speckle tracking echocardiography in the aortas of healthy children. Methods and Results One hundred healthy White children evaluated for the screening of congenital heart disease were prospectively enrolled. Echocardiographic examinations were performed using a Vivid E 95 ultrasound system, with blood speckle tracking from a focused and zoomed view of the aortic root and the ascending aorta. Vortex position, height (mm), width (mm), sphericity index, and area (cm 2 ) were measured and indexed by body surface area. Median (interquartile range) age was 8.2 (5.6–11.0) years, median (interquartile range) weight was 28 (19–35) kg, and median (interquartile range) body surface area was 1.01 (0.79–1.16) m 2 . Vortices were visualized in only a single phase of the cardiac cycle in 25 subjects—14 (56.0%) were evident in early diastole and 11 (44.0%) in late systole. Vortices visualized in diastole had a mean area of 0.27±0.1 cm 2 /m 2 , while those in systole had a mean area of 0.34±0.12 cm 2 /m 2 . In a subset of 20 patients, inter‐ and intraobserver coefficient of variation and intraclass correlation coefficients were determined and showed good reproducibility. Conclusions We demonstrate feasibility and reproducibility of blood speckle tracking and identified vortical flow patterns in the aortic root and ascending aorta in healthy children. These data may serve as a baseline for evaluating aortic flow patterns in children with congenital and acquired heart disease.

Objective Extremely low gestational age newborns (ELGANs) represent an especially vulnerable population. Herein, we aimed to determine incidence and severity of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) in extremely immature ELGANs (gestational age: 230/6–256/7 weeks). Methods In this prospective observational cohort study, we assessed BPD-PH by means of several echocardiography markers and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 3 and 12 months of chronological age. In addition, we analyzed incidence and efficacy of pharmacologic treatment for BPD-PH. Results At 3 months 15/34 ELGANs had echocardiographic evidence of BPD-PH, while at 12 months of age 6/34 still had PH. PH-targeted therapy consisted of sildenafil monotherapy in 11 and dual oral combination therapy (sildenafil and macitentan) in four ELGANs at 3 and 12 months. Conclusion 44% (15/34) of ELGANs developed BPD-PH. All received PH-targeted pharmacotherapy at 3 months, leading to hemodynamic improvements at 12 months in most infants.

Background: 2D speckle tracking echocardiography (STE) atrial strain (ε) analysis in children is gaining interest; however, pediatric nomograms remain limited. Comparison among conventional software's (designed for left ventricle and adapted to atria and using R-gating analysis) and new software's (designed for atria and allowing for both R- and P-gating) are lacking. The present study aims to establish pediatric nomograms for atrial ε using an atrial dedicated software and to compare values obtained by (a) R- and P-gating and, (b) R-gating with new and conventional software. Methods: Echocardiographic measurements included STE left (LA) and right (RA) atrial longitudinal reservoir, conduit and contractile ε. Age/weigh/height/heart rate, and body surface area (BSA) were used as independent variables in the statistical analysis. Results: In all, 580 healthy subjects (age range, 31 days-18 years; mean age 7.5 years; median age 7.1 years; inter-quartile range, 4.3–10.7 months; 45.5% female) were included. Feasibility of atrial ε measurements was high (98.9–96.8%). At lower age, atrial conduit ε was lower (p

Background: Echocardiographic screening of anomalous coronary artery origin is of increasing interest for children participating in sport activities. However, criteria to define normal coronary artery origins in children are poorly defined. Thus, the aim of the present investigation is to define the normal origin and angle of emergence of coronary arteries by echocardiography in healthy children. Materials and methods: The distances of the left main and right coronary artery (LMCA, RCA) origins from the aortic annulus were measured in the parasternal long-axis view (LAX). The angle of coronary artery emergence was measured in the parasternal short-axis view (SAX). Results: A total of 700 healthy subjects (mean age: 9.53 ± 5.95 years; range: 1 day–17.98 years) were prospectively enrolled. The distance of the RCA and LMCA from the aortic annulus correlated with body surface area, and nomograms (Z-scores) were generated. The RCA origin was below the sinotubular junction (STJ) in 605 patients (86.43%), at the STJ in 66 patients (9.43%), and above the STJ in 29 patients (4.14%). The LMCA origin was below the STJ in 671 patients (95.86%), at the STJ in 12 patients (1.71%), and above the STJ in 17 patients (2.43%). With respect to the RCA, an emergence angle < 18.5° in the SAX predicted a high take-off. with a sensitivity of 98.3% and a specificity of 93.1% (AUC 0.998). With respect to the LMCA, an emergence angle > 119.5° in the SAX predicted a high take-off, with a sensitivity of 70.6% and a specificity of 82.4% (AUC 0.799). Conclusion: This study establishes nomograms for LMCA and RCA origin in standard echocardiographic projections in healthy children.

In 2019, the European Paediatric Pulmonary Vascular Disease Network (EPPVDN) developed a PH risk score to assess the risk and severity of pulmonary hypertension (PH) in children and young adults. We conducted a prospective observational study to validate the EPPVDN paediatric PH risk score by means of cardiac magnetic resonance imaging (CMR) and echocardiography.During the same inpatient stay, the invasive and noninvasive EPPVDN PH risk scores were determined, and a protocol-driven CMR study was performed on 20 PAH children. Subsequently, we correlated the risk scores with imaging variables derived from CMR and echocardiography, including strain. Further, we applied the risk score to nine children with PAH who received add-on selexipag therapy. Before and approximately six months after selexipag start, the risk score and echocardiographic RV strain were determined and delta changes of both were correlated.We found strong correlations of conventional CMR (r = 0.69-0.88), CMR strain (r = 0.71-0.88), advanced echocardiographic (r = 0.65-0.88) and echocardiographic strain variables (r = 0.67-0.86) with the EPPVDN PH risk scores (p .006). In the selexipag cohort, the change in echo-derived RV free wall strain correlated well with the change in the invasive higher risk score (r = 0.72, p = .028).We demonstrate strong correlations of outcome-relevant CMR and echocardiographic variables with the EPPVDN PH risk scores, and thus validated the score via independent methods. To achieve broad and easy access, we developed a calculator for the risk score as a web application (www.pvdnetwork.org/pedphriskscore). The novel EPPVDN PH risk score will be useful in routine clinical care and can now be applied in larger paediatric PH studies.

BackgroundAn accurate assessment of the right and left ventricle and their interaction is important in pediatric pulmonary hypertension (PH). Our objective was to provide normal reference values for the right ventricular to left ventricular endsystolic (RV/LVes) ratio and the LV endsystolic eccentricity index (LVes EI) in healthy children and in children with PH.MethodsWe conducted an echocardiographic study in 769 healthy children (median age: 3.36 years; range: 1 day—18 years) and validated abnormal values in 44 children with PH (median age: 2.1 years; range: 0.1 months—17.7 years). We determined the effects of gender, age, body length, body weight, and body surface area (BSA) on RV/LVes ratio and LVes EI values. The RV/LVes ratio and LVes EI were measured from the parasternal short axis view between papillary muscle from the endocardial to endocardial surfaces.ResultsBoth, the RV/LVes ratio and the LVes EI were highly age-dependent: (i) neonates RV/LVes ratio [median 0.83 (range 0.53–1.37)], LVes EI [1.21 (0.92–1.45)]; (ii) 12–24 months old: RV/LVes ratio: [0.55 (0.35–0.80)], LVes EI: [1.0 (0.88–1.13)]; iii) 18th year of life RV/LVes ratio: [0.53 (0.32–0.74)], LVes EI: [1.0 (0.97–1.07)]. Healthy neonates had high LVes EI and RV/LVes ratios, both gradually decreased within the first year of life and until BSA values of about 0.5 m2, body weight to about 15 kg and body length to about 75 cm, but were almost constant thereafter. Children (>1 year) and adolescents with PH had significantly higher RV/LVes ratio (no PH: median 0.55, IQR 0.49–0.60; PH: 1.02, 0.87–1.26; p < 0.001) and higher LVes EI values (no PH: 1.00, 0.98–1.00; PH: 1.53, 1.26–1.71; p < 0.001) compared to those without PH. To predict the presence of PH in children > 1 year, we found the following best cutoff values: RV/LVes ratio ≥ 0.67 (sensitivity: 1.00, specificity: 0.95) and LVes EI ≥ 1.06 (sensitivity: 1.00, specificity: 0.97).ConclusionWe provide normal echocardiographic reference values of the RV/LVes ratio and LVes EI in healthy children, as well as statistically determined cutoffs for the increased values in children with PH.

Background: Applications of atrial speckle tracking echocardiography (STE) strain (ε) analysis in pediatric cardiac surgery have been limited. This study aims to evaluate the feasibility of atrial STE ε analysis and the progression of atrial ε values as a function of post-operative time in children after pediatric cardiac surgery. Methods: 131 children (mean 1.69 ± 2.98; range 0.01–15.16 years) undergoing cardiac surgery were prospectively enrolled. Echocardiographic examinations were performed pre-operatively and at 3 different post-operative intervals: Time 1 (24–36 h), Time 2 (3–5 days), Time 3 (>5 days, before discharging). The right and left atrium longitudinal systolic contractile (Ct), Conduit (Cd), and Reservoir (R) ε were evaluated with a novel atrial specific software with both P- and R-Gating methods. One hundred and thirty-one age-matched normal subjects (mean 1.7 ± 3.2 years) were included as controls. Results: In all, 309 examinations were performed over the post-operative times. For each post-operative interval, all STE atrial ε parameters assessed were significantly lower compared to controls (all p < 0.0001). The lowest atrial ε values were found at Time 1, with only partial recovery thereafter (p from 0.02 to 0.04). All atrial ε values at discharge were decreased compared to the controls (all p < 0.0001). Significant correlations of the atrial ε values with cardio-pulmonary-bypass time, left and right ventricular ε values (p < 0.05), and ejection fraction (p < 0.05) were demonstrated. Conclusions: Atrial ε is highly reduced after surgery with only partial post-operative recovery in the near term. Our study additionally demonstrates that post-surgical atrial and ventricular ε responses correlated with each other.

Right ventricular (RV) function is important for clinical status and outcomes in children and adults with congenital heart disease (CHD). In the normal RV, longitudinal systolic function is the major contributor to global RV systolic function. A variety of factors contribute to RV failure including increased pressure- or volume-loading, electromechanical dyssynchrony, increased myocardial fibrosis, abnormal coronary perfusion, restricted filling capacity and adverse interactions between left ventricle (LV) and RV. We discuss the different imaging techniques both at rest and during exercise to define and detect RV failure. We identify the most important biomarkers for risk stratification in RV dysfunction, including abnormal NYHA class, decreased exercise capacity, low blood pressure, and increased levels of NTproBNP, troponin T, galectin-3 and growth differentiation factor 15. In adults with CHD (ACHD), fragmented QRS is independently associated with heart failure (HF) symptoms and impaired ventricular function. Furthermore, we discuss the different HF therapies in CHD but given the broad clinical spectrum of CHD, it is important to treat RV failure in a disease-specific manner and based on the specific alterations in hemodynamics. Here, we discuss how to detect and treat RV dysfunction in CHD in order to prevent or postpone RV failure. ispartof: CARDIOVASCULAR DIAGNOSIS AND THERAPY vol:10 issue:5 pages:1625-1645 ispartof: location:China status: published

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families.

Background:Thrombocytopenia is a risk factor for patent ductus arteriosus. Immature and mature platelets exhibit distinct haemostatic properties; however, whether platelet maturity plays a role in postnatal, ductus arteriosus closure is unknown.Methods:In this observational study, counts of immature and mature platelets (=total platelet count − immature platelet count) were assessed on days 1, 3, and 7 of life in very low birth weight infants (Results:Counts of mature platelets did not differ on day 1 in infants with (n = 24) and without (n = 45) haemodynamically significant patent ductus arteriosus, while infants with significant patent ductus arteriosus exhibited lower counts of mature platelet on postnatal days 3 and 7. Relative counts of immature platelets (fraction, in %) were higher in infants with patent ductus arteriosus on day 7 but not on days 1 and 3. Receiver operating characteristic curve analysis unraveled associations between both lower mature platelet counts and higher immature platelet fraction (percentage) values on days 3 and 7, with haemodynamically significant ductus arteriosus. Logistic regression analysis revealed that mature platelet counts, but not immature platelet fraction values, were independent predictors of haemodynamically significant patent ductus arteriosus.Conclusion:During the first week of postnatal life, lower counts of mature platelets and higher immature platelet fraction values are associated with haemodynamically significant patent ductus arteriosus. Lower counts of mature platelet were found to be independent predictors of haemodynamically significant patent ductus arteriosus.

Aim Cardiac function is a major factor for tissue perfusion and therefore may affect the tissue oxygen saturation. Aim was to analyse possible associations between cardiac function parameters and cerebral and peripheral tissue oxygenation in neonates on the first day after birth. Methods For the present study, we analysed secondary outcome parameters of a previously performed prospective single centre observational study. The prospective study was conducted at the Medical University of Graz, Austria between September 2011 and June 2013. We included preterm and term neonates who were admitted to the neonatal intensive care unit and in whom simultaneous near‐infrared spectroscopy measurements and echocardiography were obtained on the first day after birth. Cardiac function parameters were correlated to cerebral and peripheral tissue oxygen saturation and cerebral and peripheral fractional tissue oxygen extraction at the time of echocardiography. Results A total of 60 neonates of whom 47 were preterm and 13 were term (median gestational age: 34; IQR 33‐35 weeks, mean birth weight: 2276 ± 774 grams) were included. There were no statistically significant correlations between cardiac function parameters and regional tissue oxygenation parameters. Conclusion In the present study, we found no correlation between regional tissue oxygenation and parameters of cardiac function in cardio‐circulatory stable neonates on the first day after birth.

Echocardiographic determination of the right ventricular end-systolic remodeling index (RVES RI) has clinical value for the assessment of pulmonary hypertension (PH) in adults. We aim to determine RVES RI values in pediatric PH and to correlate RVES RI data with echocardiographic variables and NYHA functional class (FC). Prospective echocardiography study in 49 children with PH. The 49 matched control subjects were chosen from 123 healthy children used to construct pediatric normal reference values. The associations with invasive hemodynamic variables were also investigated in a validation cohort of 12 PH children and matched controls. RVES RI was increased in children with PH vs. healthy controls (1.45 ± 0.16 vs. 1.16 ± 0.06; p

We reviewed the recent literature for echocardiographic assessment of mitral valve abnormalities in children. A literature search was performed within the National Library of Medicine using the keywords “mitral regurgitation and/or stenosis, children.” The search was refined by adding the keywords “echocardiographic definition, classification, and evaluation.” Thirty-one studies were finally included. Significant advances in echocardiographic imaging of mitral valve defects, mainly due to the implementation of three-dimensional technology, contribute to a better understanding of the underlying anatomy. However, heterogeneity between classification systems of mitral valve disease severity is a serious problem. For regurgitant lesions, there is only very limited evidence from small studies that support the adoption of quantitative/semi-quantitative indexes commonly employed in adults. Despite the lack of evidence base, qualitative evaluation of regurgitation severity is often employed. For stenotic lesions, no clear categorisation based on trans-valvular echocardiography-derived “gradients” has been consistently applied to define mild, moderate, or severe obstruction across different paediatric age ranges. Quantitative parameters such as valve area have also been poorly validated in children. Adult recommendations are frequently applied without validation for the paediatric age. In conclusion, significant advances in the anatomical evaluation of mitral valve diseases have been made, thanks to three-dimensional echocardiography; however, limitations remain in the quantitative/semi-quantitative estimation of disease severity, both with respect to valvular regurgitation and stenosis. Because adult echocardiographic recommendations should not be simply translated to the paediatric age, more specific paediatric guidelines and standards for the assessment of mitral valve diseases are needed.

Nitric oxide donors (NO-donors) have been shown to have therapeutic potential (e.g., ischemia/reperfusion injury). However, due to their release rate/antiplatelet properties, they may cause bleeding in patients. We therefore studied the antiplatelet effects of the two different NO-donors, i.e., S-NO-Human Serum Albumin (S-NO-HSA) and Diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate) in whole blood (WB) samples. WB samples were spiked with S-NO-HSA or DEA-NONOate (100 µmol/L or 200 µmol/L), and the NO release rate (nitrite/nitrate levels via HPLC) and antiplatelet efficacy (impedance aggregometry, platelet function analyzer, Cone-and-platelet analyzer, thrombelastometry) were assessed. S-NO-HSA had a significantly lower NO release compared to equimolar concentrations of DEA-NONOate. Virtually no antiplatelet action of S-NO-HSA was observed in WB samples, whereas DEA-NONOate significantly attenuated platelet function in WB. Impedance aggregometry measurements revealed that Amplitudes (slope: −0.04022 ± 0.01045 ohm/µmol/L, p = 0.008) and Lag times (slope: 0.6389 ± 0.2075 s/µmol/L, p = 0.0051) were dose-dependently decreased and prolonged by DEA-NONOate. Closure times (Cone-and-platelet analyzer) were dose-dependently prolonged (slope: 0.3738 ± 0.1403 s/µmol/L, p = 0.0174 with collagen/ADP coating; slope: −0.5340 ± 0.1473 s/µmol/L, p = 0.0019 with collagen/epinephrine coating) by DEA-NONOate. These results in WB further support the pharmacological potential of S-NO-HSA as an NO-donor due to its ability to presumably prevent bleeding events even at high concentrations up to 200 µmol/L.

The incidence of thrombosis increases with aging. We investigated the coagulatory/haemostatic system across the ages and tested the hypothesis that older persons have a hypercoagulable state compared to younger persons at rest, and that standing up (orthostasis) leads to greater changes in coagulation in older persons. In total, 22 older and 20 young participants performed a 6 min sit-to-stand test (orthostatic challenge). Blood was collected prior to and at the end of standing and haemostatic profiling was performed via thrombelastometry (TEM), calibrated automated thrombogram (CAT) and standard coagulation assays. At baseline, three CAT-derived values indicated enhanced capability to generate thrombin in older participants. However, other measured parameters did not suggest a hypercoagulable state in older participants: prolonged TEM-derived coagulation times (295 vs. 209 s, medians, p = 0.0025) and prothrombin times (103 vs. 114%, medians, p = 0.0087), as well as lower TF levels (440 vs. 672 pg/mL, medians, p = 0.0245) and higher t-PA levels (7.3 vs. 3.8 ng/mL, medians, p = 0.0002), indicative of enhanced fibrinolytic capability, were seen. Younger participants were more sensitive to the orthostatic challenge: CAT-derived endogenous thrombin potentials (ETPs) were only increased in the young (1337 to 1350 nM.min, medians, p = 0.0264) and shortening of PTs was significantly higher in the young vs. older participants (p = 0.0242). Our data suggest that the increased thrombosis propensity in older persons is not primarily attributable to a hyperactive coagulation cascade but may be due to other pathologies associated with aging.

BACKGROUND: The immediate transition from foetus to neonate includes substantial changes especially concerning the cardiovascular system. As sex related differences have been shown in cardiovascular medicine, this topic warrants further investigation in neonatology. Aim: The aim of this present study was to measure cardiac output (CO) and cerebral oxygenation (cTOI) non-invasively in term neonates and to investigate potential sex related differences between female and male neonates after birth. METHODS: This is a mono-centric prospective observational study. For CO-measurements, the electrical velocimetry method was used. The pulse oximetry for arterial oxygen saturation and heart-rate measurements was placed on the right hand or wrist. cTOI was measured using a NIRO 200NX monitor. The near-infrared spectroscopy probe was positioned on the right side of forehead in each infant. Monitoring started at minute 1 and was continued until minute 15 after birth. At minutes 5, 10, and 15 after birth, CO was calculated as an average out of six 10-second periods. RESULTS: 99 term neonates were enrolled. In our study population, we could identify 54 female and 45 male neonates. Males had higher cardiac output compared to females throughout the observational period, with a significant difference in minute 15 after birth (217, 95% CI: 203–231 mL/kg/min versus 178, 95% CI: 163–192 mL/kg/min; P

Pulmonary hypertension (PH), and especially pulmonary arterial hypertension (PAH), are chronic, progressive, and fatal conditions for which - apart from bilateral lung transplantation - there is currently no cure. However, recently developed, so-called "targeted" ("advanced") PAH medications, are now approved for adult PAH, and have improved quality of life and survival of affected children and adults. In 2020, two prospective pediatric observational studies on add-on macitentan and selexipag, respectively, have been published. Due the lack of approved pediatric PAH-medications, the well-founded rationale for combination therapy in childhood, and the absence of serious adverse effects, advanced pharmacotherapy should not be withheld from young PH patients. Such an "off-label use" of PAH-targeted medications in children with PH, and its financial reimbursement by health insurances, are urgently needed. The decision on the specific, vasoactive pharmacotherapy should be made by a PH expert with sufficient experience in the diagnosis and treatment of children with PH - followed by close out-patient monitoring. Combination pharmacotherapy should include the option of combining drugs of all substance classes (phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, drugs targeting prostacyclin pathways, and calcium channel blockers in select cases) - including "off-label, pediatric drug formulations". Neither the lack of approval for modern PAH drugs directed against PAH nor the limited evidence-based study data available for children, should preclude PH expert centers to offer these therapies early and in combination to young patients with progressive PH, in order to improve exercise capacity, quality of life, and survival.

Zusammenfassung Eine pathologische Druckerhöhung im pulmonalen Gefäßsystem (pulmonale Hypertonie, PH) wurde bisher definiert durch einen invasiv gemessenen mittleren pulmonalarteriellen Druck (mPAP) ≥25 mm Hg in Ruhe. Auf dem 6th World Symposium on Pulmonary Hypertension (WSPH) in Nizza 2018 wurde eine neue Definition der PH vorgeschlagen, die die Senkung der Obergrenze des normalen mPAP von 24 auf 20 mm Hg beinhaltet. Obwohl keine Evidenz aus pädiatrischen Studien hierfür vorliegt, wurde diese neue PH-Definition (mPAP >20 mm Hg) aus Gründen der Einheitlichkeit auch von der pädiatrischen „Task Force“ des WSPH 2018 übernommen. Die vorliegende Stellungnahme der Arbeitsgemeinschaft Pulmonale Hypertonie (AGPH) der Deutschen Gesellschaft für Pädiatrische Kardiologie und angeborene Herzfehler e. V. (DGPK) erläutert die zugrunde liegende Rationale und mögliche Konsequenzen dieser Definitionsänderung. Insbesondere stellt sie klar, dass diese Änderung der Definition aktuell keinen Einfluss auf die Verschreibung von Medikamenten zur gezielten spezifischen Therapie der pulmonalarteriellen Hypertonie hat.

In the last few years, multiple echocardiographic nomograms have been published. However, normal values calculated in the general population are not applicable to athletes, whose hearts may be enlarged and hypercontractile. Accordingly, athletes require specific nomograms. Our aim is to provide a critical review of echocardiographic nomograms on two-dimensional (2D) measures for athletes. We performed a systematic search in the National Library of Medicine for Medical Subject Headings and free text terms including echocardiography, athletes, normal values and nomograms. The search was refined by adding the keywords heart, sport, elite, master, children and young. Twenty-eight studies were selected for the final analysis. Our research revealed that currently available ranges of normality for athletes reported by different authors are quite consistent, with limited exceptions (e.g. atria, aorta). Numerical and methodological limitations, however, emerged. Numerical limitations included a limited sample size (e.g.

While the current definition of pulmonary hypertension (PH) is still based on haemodynamic variables, transthoracic echocardiography is the most important diagnostic clinical tool for the first assessment and evaluation of a patient, in whom PH is suspected. In addition, it is the most important clinical modality in long term follow-up and the utility of echocardiography has widely been demonstrated in patients with PH. Echocardiography not only reveals the underlying cardiac morphology and diagnosis of any associated cardiac defects. In most patients with PH right ventricular (RV) pressure estimation is feasible. In addition, ventricular systolic and diastolic function, as well as ventricular-ventricular interactions of both ventricles can be assessed by using echocardiography. Maximizing the use of echocardiography by reporting several measures to gain information and quantitatively describe the parameters, that are linked to prognosis, seem particularly appealing in these children, in whom other advanced imaging modalities requiring anaesthesia is associated with a considerable risk. Herein we provide a practical approach and a concise and clinically applicable echocardiographic guidance and present basic variables, which should be obtained at any assessment. Moreover, we present additional advanced echocardiographic measures, that can be applied in a research or clinical setting when progressive PH needs a deeper insight to assess heart function, estimation of pulmonary artery pressures among others, by echocardiography. Finally, clinically relevant studies in view of the prognostic properties with a focus on the most important echocardiographic variables in pediatric PH are summarized.

BACKGROUND: Macitentan, a dual endothelin receptor antagonist (ERA), was approved in 2014 for the treatment of adults with idiopathic pulmonary arterial hypertension (PAH). Once-per-day dosing and low potential hepatic toxicity make macitentan an appealing therapeutic option for children with PAH, but reports on its use in pediatric patients are still lacking. METHODS: Prospective observational study of 18 children [10 male; median age: 8.5, minimum (min.): 0.6, maximum (max.): 16.8 years] with pulmonary hypertension (PH). Four of these 18 patients were treatment-naïve and started on a de novo macitentan therapy. The remaining 14/18 children were already on a PH-targeted pharmacotherapy (sildenafil or bosentan as monotherapy or in combination). Nine children who were on bosentan were switched to macitentan. We analyzed the 6-minute walking distance (6MWD), NYHA functional class (FC)/modified ROSS score, invasive hemodynamics, echocardiographic variables and the biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: The median follow up was 6 months (min.: 0.5, max.: 30). Macitentan treatment was associated with improvement of invasive hemodynamics, e.g., the ratio of mean pulmonary arterial pressure/mean systemic arterial pressure decreased from a median of 62% (min.: 30%, max.: 87%) to 49% (min.: 30%, max.: 69%), P

Background: While mitral (MV) and tricuspid valve (TV) pulsed Doppler velocities and derived gradients are commonly evaluated, data on normal pediatric values are limited. This study aimed to evaluate the normal values and physiological variability for MV and TV Doppler velocities and derived gradients in a large cohort of prospectively enrolled healthy children. Methods: The echocardiographic measurements included pulsed Doppler MV and TV E and A velocities, E deceleration times (EDT), maximal and mean gradients, and velocity time integral (VTI). Results: A total of 544 healthy subjects (median age 6.4 years, range 1 day–17.68 years) were included. MV and TV E velocity, E/A ratio, and E and A wave duration increased, while A velocity decreased with age (p < 0.001). Along with an increase in VTI, there occurred a progressive increase in maximum velocity and gradients and a decrease in mean velocities and gradients. E/A inversions were common, especially at the TV in neonates and infants. For MV, inversion in either one, two, or three consecutive beats occurred in 51.9% of neonates and 18.3% of infants, while it was rare at older ages (all p < 0.001). For TV, inversions in three consecutive beats occurred in 71.4% of neonates, while inversions in only one or two beats were more common in infants (27.3%). For TV, inversion in one or more beats, however, was not infrequent at all ages. Conclusions: We report normal values and patterns of normality and physiological variability for MV and TV inflow Doppler from a large population of healthy children.

Lower body negative pressure (LBNP) application simulates hemorrhage. We investigated how seasons affect coagulation values at rest and during LBNP. Healthy participants were tested in cold (November&ndash, April) and warm (May&ndash, October) months. Following a 30-min supine period, LBNP was started at &minus, 10 mmHg and increased by &minus, 10 mmHg every five minutes until a maximum of &minus, 40 mmHg. Recovery was for 10 min. Blood was collected at baseline, end of LBNP, and end of recovery. Hemostatic profiling included standard coagulation tests, calibrated automated thrombogram, thrombelastometry, impedance aggregometry, and thrombin formation markers. Seven men (25.0 &plusmn, 3.6 years, 79.7 &plusmn, 7.8 kg weight, 182.4 &plusmn, 3.3 cm height, and 23.8 &plusmn, 2.3 kg/m2 BMI) and six women (25.0 &plusmn, 2.4 years, 61.0 &plusmn, 8.4 kg weight, 167 &plusmn, 4.7 cm height, and 21.8 &plusmn, 2.4 kg/m2 BMI) participated. Baseline levels of prothrombin (FII), tissue factor (TF) and markers for thrombin generation F1+2 and the thrombin/antithrombin complex (TAT) were higher during summer. Factor VIII, prothrombin fragment 1+2 (F1+2), TAT and the coagulation time showed significant increases during LBNP in both seasons. Some calibrated automated thrombography variables (Calibrated automated thrombography (CAT): lag, time to peak (ttPeak), peak) shifted in a procoagulant direction during LBNP in summer. Red blood cell counts (RBC), hemoglobin and white blood cell counts (WBC) decreased during LBNP. LBNP application reduced prothrombin time in winter and activated partial thromboplastin time in summer. Greater levels of FII, TF, F1+2, and TAT&mdash, a more pronounced LBNP-induced procoagulative effect, especially in CAT parameters (lag time (LT), Peak, ttPeak, Velindex)&mdash, were seen in summer. These results could have substantial medical implications.

BACKGROUND: Ventricular septal flattening, frequently present in pulmonary hypertension (PH), can be quantified using eccentricity index (EI). EI has not been evaluated by concurrent echocardiography and cardiac catheterization, and traditionally does not account for post-systolic septal flattening, often seen in PH. We evaluated left ventricular (LV) shape, including a novel measure of maximal EI (EIM) to account for post-systolic septal flattening, to establish the relationship with concurrent invasive hemodynamics. METHODS: Echocardiography was performed at 2 institutions in 78 pediatric pulmonary hypertension patients during cardiac catheterization, and in 78 matched controls. From mid-papillary parasternal short-axis views, EI and right-to-left ventricular diameter ratio (RV:LV) were assessed. RESULTS: EI and RV:LV measures were significantly increased in PH compared to controls. Shape measures correlated with invasive hemodynamics and PH outcome measures (PH-related hospitalization, functional class, medical therapy escalation, and brain natriuretic peptide). End-systolic EI of 1.16 best identified the presence of PH, while an EIM of 1.42 and 1.94 best identified half-systemic and systemic PH, respectively. An EIM of 1.27 was associated with an odds ratio of 16.16 (95% CI 6.62-39.46) for PH-related hospitalization or escalation of therapy. CONCLUSIONS: Using simultaneous echocardiography and catheterization in the largest study population to date, we demonstrate that EI and RV:LV ratio correlate with invasive hemodynamics and outcomes measures, and EI can accurately define those with clinically important PH. These measures strengthen the ability of echocardiography to identify and follow pediatric PH patients, especially in the absence of methods to quantify RV systolic pressures.

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:75 issue:19 pages:2463-2477 ispartof: location:United States status: published

The European Pediatric Pulmonary Vascular Disease Network (EPPVDN) investigated the safety and efficacy of add-on selexipag, an oral prostacyclin receptor agonist approved for pulmonary arterial hypertension (PAH) in adults, in the largest, exploratory pediatric cohort to date.This is a prospective observational study of 15 consecutive children with PAH, treated with oral add-on selexipag at 3 centers. Most patients underwent cardiac catheterizations at baseline and median of 8 months follow-up. All patients had clinical, echocardiographic, and N-terminal pro b-type natriuretic peptide studies, including the EPPVDN pediatric pulmonary hypertension (PH) risk score.There was no death during the use of selexipag. Two of 15 patients ultimately underwent lung transplantation. One patient with heritable PAH died on intravenous treprostinil (off selexipag). The mean right atrial pressure, the ratio of pulmonary arterial pressure (PAP) to systemic arterial pressure (SAP) (mean PAP/mean SAP, diastolic PAP/diastolic SAP: -17%), and transpulmonary pressure gradients (TPG) (mean TPG: -17%; p0.01; diastolic TPG: -6 mm Hg; p0.05) were improved after the therapy (n = 10). Selexipag therapy was associated with a better right ventricular systolic function (tricuspid annular plane systolic excursion: +14.5%; p0.01) and functional class. Improvement was seen in non-invasive and combined invasive/non-invasive PH risk scores (lower risk: +18%-22%, higher risk: -35%-37%; p0.05). Overall, the efficacy of selexipag was variable, often with a better response in less sick patients.Oral selexipag use in children with PAH is well tolerated and safe when closely monitored. Add-on selexipag therapy improved several outcome-relevant variables in about 50% of patients and prevented disease progression in additional 27% of patients. The novel EPPVDN pediatric PH risk score indicated these drug effects properly, can be useful in clinical follow-up, and should be validated in larger prospective studies.

We discuss the currently available data on the use of the prostacyclin mimetic selexipag in children and adolescents with pulmonary arterial hypertension (PAH). Future indications may include transitioning from intravenous prostacyclin/prostacyclin analog to oral selexipag, and vice versa, or adding selexipag as a third oral PAH-targeted agent in children not responding well to dual PAH therapy.

Objective The right ventricular outflow tract (RVOT) is pivotal for adequate RV function and known to be adversely affected by elevated pulmonary arterial pressure (PAP) in adults with pulmonary hypertension (PH). Aim of this study was to determine the effects of increased RV pressure afterload in children with PH on RVOT size, function, and flow parameters. Methods We conducted a transthoracic echocardiographic study in 51 children with PH (median age: 5.3 years; range 1.5 months to 18 years) and determined the following RVOT variables: RVOT diameter, RVOT velocity time integral (VTI), ratio of tricuspid regurgitation velocity (TRV)/RVOT VTI, and RVOT systolic excursion (SE). Results In our pediatric PH cohort, the age-specific RVOT diameter z-score was higher compared to normal values. Deviation from normal RVOT diameter values increased with age, disease severity, and New York Heart Association functional class. Significant correlations were found between RVOT diameter and the RV end-diastolic area and right atrial area. The age-specific RVOT VTIz-score values were significantly lower in children with PH vs healthy controls. The TRV/RVOT VTI ratio increased with rising systolic RV pressure, while the RVOT SE was similar between PH children and control subjects. Conclusions In pediatric PH cohort, the RVOT VTI is decreased, and the TRV/RVOT VTI ratio and the RVOT diameter increased compared to healthy subjects. Assessment of RVOT variables, together with established RV parameters, allows for a comprehensive assessment of global right heart size and performance in children with PH.

Highlights • Utilization of high-frame rate blood speckle tracking echocardiography. • Left ventricular (LV) vortices were analyzed in a pediatric population. • No overall effect of congenital heart disease was observed. • LV volume and pressure overload influenced vortex localization. • Significant associations of LV morphology with vortex characteristics were found., Background High-frame rate blood speckle tracking (BST) echocardiography is a new technique for the assessment of intracardiac flow. The purpose of this study was to evaluate the characteristics of left ventricular (LV) vortices in healthy children and in those with congenital heart disease (CHD). Methods Characteristics of LV vortices were analyses based on 4-chamber BST images from 118 healthy children (median age 6.84 years, range 0.01–17 years) and 43 children with CHD (median age 0.99 years, range 0.01–14 years). Both groups were compared after propensity matching. Multiple linear regression was used to identify factors that independently influence vortex characteristics. Results Feasibility of vortex imaging was 93.7% for healthy children and 95.6% for CHD. After propensity matching, there were no overall significant differences in vortex distance to apex, distance to interventricular septum (IVS), height, width, sphericity index, or area. However, multiple regression analysis revealed significant associations of LV morphology with vortex characteristics. Furthermore, CHD involving LV volume overload and CHD involving LV pressure overload were both associated with vortices localized closer to the IVS. Conclusions LV vortex analysis using high-frame rate BST echocardiography is feasible in healthy children and in those with CHD. As they are associated with LV morphology and are modified in some types of CHD, vortices might yield diagnostic and prognostic value. Future studies are warranted to establish applications of vortex imaging in the clinical setting.

The use of linear and convex transducers is usually reserved for ultrasound imaging of vessels, abdominal organs, and lungs. However, the use of these transducers may be extended for the evaluation of thoracic structures. We describe our experience with the use of linear and convex transducers in the evaluation of the retrosternal area, which is usually difficult to visualize by conventional echocardiography and so could provide improved diagnostic information in patients after cardiac surgery.

Nomograms are essential tools for quantification in pediatric echocardiography. In the last few years, multiple sources highlight that nomograms employed for decades presented significant numerical and methodological limitations. As a result, widely different ranges of normality were generated, thus creating confusion in estimation of several cardiac diseases. New nomograms have recently been generated, overcoming some of the gaps of previous research: wider sample sizes (including neonates/infants), solid statistical/methodological plan, and availability of new data (chamber dimensions, many functional parameters). In particular, robust two-dimensional nomograms covering a wide spectrum of cardiac measurements have recently become available. Significant advances have been made for functional data (i.e. diastolic and deformation indexes) but a few limitations still exist. These include numerical issues (sample size of below 400 subjects) and methodological pitfalls (heterogeneous data normalization/expression). Despite these limitations, however, actual nomograms for functional data present quite reproducible intervals of normality with the exception of neonates and infants. In conclusion, great advances have been made during the last years. A few basic rules for the building of nomograms have been established (i.e. inclusion/exclusion criteria, measurement standardization), while others (i.e. the sample size, the way to express/normalize data, statistical requirements) are basically defined but still require standardization. New pediatric echocardiographic nomograms of good quality are easily accessible due to new electronic tools (online calculators, apps for smart-phone/tablets). Studies are ongoing to generate wider, comprehensive and multi-ethnic nomograms and to evaluate new parameters (e.g. three-dimensional parameters).

We provide a practical approach on the initial assessment and diagnostic work-up of children and adolescents with pulmonary hypertension (PH). Transthoracic echocardiography (TTE) often serves as initial study tool before invasive cardiac catheterization. Misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences, or unnecessary invasive diagnostics that have inherited risks. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardized TTE approach, determining conventional and novel echocardiographic variables, may allow early diagnosis and treatment in paediatric PH. Cardiac magnetic resonance imaging and computed tomography represent important non-invasive imaging modalities, that together with TTE may enable comprehensive assessment of ventricular function and pulmonary hemodynamics. Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterization laboratory is still the gold standard for the diagnosis of PH and pulmonary hypertensive vascular disease (PHVD) in children and for the initiation of specific PH therapy. We suggest the regular assessment of prognostic TTE variables as part of a standardized approach for initial diagnosis of children with PH. Overreliance on any single TTE variable should be avoided as it detracts from the overall diagnostic potential of a standardized TTE examination for PH.

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient’s age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group “pulmonary hypertension, heart failure and transplantation” has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

Objectives Bleeding is a common, serious, and often subtle complication after total cavopulmonary connection surgery. The aim of the present study was to assess the incidence of retrosternal clots after surgery, which were searched for systematically with transthoracic ultrasound. Design Retrospective study. Setting Single center. Participants Total cavopulmonary surgeries were reviewed from January 2016 to May 2019. Interventions Thoracic ultrasound with careful evaluation of the retrosternal area was performed at different postoperative times (12-36 hours, 5-7 days, and before discharge) as completion of routine echocardiography. Measurements and Main Results Among 37 children undergoing total cavopulmonary connection (mean age 5.5 ± 1.8 years [range 2.4-11.7]; mean body surface area 0.7 ± 0.1 m2 [range 0.3-1.6 m2]), retrosternal clots were detected in 18 (48.6%). Of these, 7 (13.5%) had small clots ( 1 cm- 2- 3 cm). Four of the 6 detected large clots required surgical revision, and in the other 2 patients, the clots were not treated because the patients’ conditions were clinically stable. When 3 major groups (group 1—no or small clots, group gropu 2 are small to moderate or moderate, group 3—large clots) were evaluated, no significant differences were noted in age, body surface area, CPB time, conduit type, or the number of previous surgeries. Conclusions With thoracic ultrasound diagnosis, existence of retrosternal clots was found to be very common after total cavopulmonary connection. Most clots were small or moderate with no clinical effect; however, large clots that required redo surgery also were detected.

Background Automated detection of heart murmurs with computer-aided auscultation is not yet in clinical routine use. Aim of this study was to test sensitivity and specificity of a novel prototype algorithm in automated detection of heart murmurs from digitally recorded phonocardiograms in neonates admitted at the Neonatal Intensive Care Unit. Methods In a prospective pilot observational study from November 2012 to December 2013 auscultations by pediatricians and computer aided auscultation were performed within 12 hours of neonatal echocardiography. Echocardiography was defined as pathological when resulting in any clinical consequences or causing murmur. Phonocardiograms and auscultation were defined as pathological if a murmur was detected. Phonocardiograms were analyzed offline with a novel algorithm prototype (CSD Labs, Graz, Austria) for detection of murmurs in neonates in a first run and with an optimized algorithm in a second run and were compared with echocardiography. Sensitivity and specificity of auscultation by pediatrician and computer aided auscultation were analyzed. Results Thirty-six neonates (gestational age: 36±3 weeks) were included. Twenty-three (64%) neonates had pathological or murmur causing findings in echocardiography (positive echocardiography). Sensitivity and specificity of auscultation by pediatrician were 17% and 100%, respectively. In comparison to auscultation by pediatrician sensitivity of first run and second run were significantly higher with 70% and 83%, respectively. Specificity of first run and second run were 77% and 85%, respectively. Conclusions Phonocardiogram analysis using the novel algorithm prototype had a higher sensitivity than auscultation by pediatrician in detecting positive echocardiography findings in neonates.

The clinical value of determination of right ventricular (RV) function in adults using echocardiographic determination of the subcostal tricuspid annular plane systolic excursion (S-TAPSE) has previously been reported. We aim to provide representative, normal reference values for S-TAPSE in the pediatric age group. Moreover, validation of abnormal S-TAPSE values in children with impaired RV function, such as pulmonary hypertension (PH), is intended.We propose a prospective echocardiographic study in 658 healthy children and in 27 children with PH (age: 1 day to 18 years; BSA 0.2-2.0 mS-TAPSE values ranged from a mean of 0.65 ± 0.16 cm in healthy neonates to 1.79 ± 0.33 cm in 18-year-old healthy adolescents. S-TAPSE values increased with increasing age (P = 0.841, P0.001), body weight (P = 0.852, P0.001), body length (P = 0.846, P0.001), and BSA (P = 0.851, P0.001) in a nonlinear way in our healthy patients group. No difference in healthy male and female patients could be observed. In our 27 patients with PH (age range: 0.6 to 15.7 years) the median BSA specific S-TAPSE z-score ranged from -3.24 to 1.10, depending on restraint of RV function.The provided S-TAPSE normal reference values and z-scores may assist to identify children with impaired RV function. Abnormal S-TAPSE values will help to identify impaired RV function in pediatric patients with PH.

Objective To determine the difference in vessel measurements, signal-to-noise ratio (SNR), and voxel size between contrast-enhanced and noncontrast magnetic resonance techniques in patients with coarctation of the aorta (CoA). Materials and methods In 39 patients, vessel size, SNR, and voxel size were compared in cine magnetic resonance imaging (MRI), gadolinium-free magnetic resonance angiography (Gd-free MRA), and contrast-enhanced MRA (ce-MRA). Results There was no significant difference in measurement and SNR, but there was a significant difference in voxel size ( P Conclusions Our results show that, in CoA patients, monitoring of vessel size using cine MRI and Gd-free MRA is equivalent to ce-MRA while being less invasive.

Transthoracic echocardiography (TTE) is a useful method for non-invasive screening of patients at risk of pulmonary hypertension (PH). Since TTE often serves as the initial study before invasive cardiac catheterisation, misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences for the patients, or unnecessary invasive diagnostics that have inheriting risks. Due to the heterogeneous anatomy in congenital heart disease, particularly the assessment of myocardial function in children with PH is challenging. Here, we present recommendations on the use of TTE in the screening, diagnosis and follow-up of patients with PH, and discuss the limitations of this non-invasive imaging technique. This expert consensus statement focuses on key TTE variables used to determine the pressure in the pulmonary artery, myocardial contractility and systolic and diastolic function of the RV and LV. A particular focus is on the TTE assessment of RV function and geometry. According to the published data on the application of TTE in PH in childhood, we suggest a structured approach for non-invasive assessment of pulmonary artery pressure and myocardial function that may help to identify patients with early ventricular deterioration and their response to advanced pharmacotherapy. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardised TTE approach, determining conventional and several more novel echocardiographic variables may allow early diagnosis and treatment, better recognition of disease progression and guide tailored therapy.