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RATIONALE: There is currently no data supporting specific dosing and weaning strategies for parental prostanoid therapy in children with pulmonary arterial hypertension (PAH).OBJECTIVES: To describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome.METHODS: From an international multicenter cohort of 275 children with PAH, 98 patients that received IV/SC prostanoid therapy were retrospectively analyzed.RESULTS: IV/SC prostanoids were given as monotherapy (20%), or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2-136 ng/kg/min. During follow up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent ROC analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure (mPAP)25 ng/kg/min), early start after diagnosis and combination with other PAH-targeted drugs were associated with better transplant-free survival.CONCLUSIONS: Early initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe on the long-term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy.

Objective The Norwood neoaortic arch biomechanical properties are abnormal due to reduced vessel wall compliance and abnormal geometry. Others have previously described neoaortic geometric distortion by the degree of diameter reduction (tapering) and associated this with mismatched ventricular-neoaortic coupling, abnormal flow hemodynamic parameters, and worse patient outcome. Our purposes were to investigate the influence of neoaortic tapering (ie, diameter reduction) on flow-mediated viscous energy loss (EL') in post-Norwood palliated hypoplastic left heart syndrome patients, and correlate flow-geometry with single ventricle power generation. Methods Twenty-six palliated hypoplastic left heart syndrome patients underwent comprehensive cardiac evaluation with 4-dimensional-flow magnetic resonance imaging. Patients were grouped into high- (group H, n = 13) and low- (group L, n = 13) degree neoaortic tapering using the median cutoff value of neoaortic diameter variance. EL' was calculated along standardized segments using 4-dimensional-flow magnetic resonance imaging. Flow-mediated power loss as a percentage of total power generated by the single ventricle was determined. Results Group H had a higher prevalence of abnormal recirculating flow in the neoaorta and elevated neoaortic EL' in the ascending aorta (1.0 vs 0.6 mW; P = .004). Group H EL' was increased across the entire thoracic aorta (2.6 vs 1.3 mW; P = .002) and accounted for 0.7% of generated ventricular power versus 0.3% in group L (P = .024). EL' directly correlated with the degree of ascending aortic dilation (R = 0.49; P = .012). Conclusions Patients with high degree neoaortic tapering have more perturbed flow through the neoaorta and increased EL'. Flow-mediated energy loss due to abnormal flow represents irreversibly wasted power generated by the single right ventricle. In patients with high-degree neoaortic tapering, EL' was more than 2-fold greater than low-degree tapering patients. These data suggest that oversizing the Norwood neoaortic reconstruction should be avoided and that patients with distorted neoaortic geometry may warrant increased surveillance for single-ventricle deterioration.

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

Background: Diastolic pulmonary arterial pressure (dPAP) is regarded to be less sensitive to flow metrics as compared to mean PAP (mPAP), and was therefore proposed for the assessment of a precapillary component in patients with postcapillary pulmonary hypertension (PH). To analyze the diagnostic and prognostic impact of dPAP in patients with pure precapillary PH, we purposed to compare the correlation between dPAP and mPAP, as well as hemodynamically-derived calculations [ratio of PAP to systemic arterial pressure (PAP/SAP), pulmonary vascular resistance index (PVRI), transpulmonary gradient (TPG)], using both dPAP and mPAP, at rest and during acute vasoreactivity testing (AVT) in children with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH). Furthermore, we aimed to assess the association of these metrics (at baseline and changes after AVT) with transplant-free survival.Methods: We conducted a retrospective analysis of the TOPP (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) registry including 246 IPAH/HPAH patients. Of these, 45 children (18.3%) died, and 13 (5.3%) received lung transplantation during the observation period.Results: dPAP and mPAP-derived variables showed almost linear relationship. Higher mPAP/mSAP, and dPAP-/mPAP-derived PVRI at rest was associated with time to death/transplantation. At maximum AVT-response, the decrease of dPAP and mPAP, diastolic pulmonary gradient (DPG) and TPG, as well as dPAP/dSAP and mPAP/mSAP was associated with time to death/transplantation, showing higher significance than corresponding baseline values. Remarkably, no predictive value was found for PVRI-reduction during AVT, neither dPAP- nor mPAP-derived.Conclusions: There is a strong relationship between dPAP and mPAP-derived variables. According to our results, hemodynamics during AVT (irrespectively of dPAP- or mPAP-derived) may have more prognostic implications than resting hemodynamics in children with IPAH/HPAH, except for PVRI.

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH (n = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and 1) standard PAH indices from catheterization, 2) cardiac MRI hemodynamics, and 3) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume (R = 0.45, P = 0.04). MMP-9 levels were significantly associated with stroke volume (R = −0.49, P = 0.03) and pulmonary vascular resistance (R = 0.49, P = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change (R = −0.79, P < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity (R = 0.51, P = 0.03) and backward compression wave (R = 0.52, P = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices. NEW & NOTEWORTHY Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.

OBJECTIVE: To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension in a large, multicenter pediatric pulmonary hypertension registry. STUDY DESIGN: We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with Down syndrome and children without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome. RESULTS: Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. The median age at diagnosis of pulmonary hypertension in patients with Down syndrome was 0.49 year (IQR, 0.21–1.77 years), similar to that in patients without Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with Down syndrome and those without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%; repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). Pulmonary hypertension resolved in 43% after 3 years, associated with a diagnosis of pulmonary hypertension at age

This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient’s current endothelin receptor antagonist therapy) study included pediatric patients aged

Cor Pulmonale or right ventricular (RV) dysfunction due to pulmonary disease is an expected complication of COPD resulting primarily from increased afterload mediated by chronic alveolar hypoxemia and resulting hypoxic pulmonary vasoconstriction. Early detection of elevated RV afterload has been previously demonstrated by visualization of abnormal flow patterns in the proximal pulmonary arteries. Prior analysis of helicity in the pulmonary arteries in pulmonary hypertension patients has demonstrated a strong association between helicity and increased RV afterload. However, these flow hemodynamics have yet to be fully explored in patients with COPD. We hypothesized that patients with COPD will have abnormal pulmonary flow as evaluated by 4D-Flow MRI and associated with RV function and pulmonary arterial stiffness. Patients with COPD (n = 15) (65 years ± 6) and controls (n = 10) (58 years ± 9) underwent 4D-Flow MRI to calculate helicity. The helicity was calculated in the main pulmonary artery (MPA) and along the RV outflow tract (RVOT)-MPA axis. Main pulmonary arterial stiffness was measured using the relative area change (RAC). We found COPD patients had decreased helicity relative to healthy controls in the MPA (19.4 ± 7.8vs 32.8 ± 15.9, P = 0.007) and reduced helicity along the RVOT-MPA axis (33.2 ± 9.0 vs 43.5 ± 8.3, P = 0.010). Our investigation indicates a strong association between helicity along the MPA-RV outflow tract axis and RV function and suggests that 4D-Flow MRI might be a sensitive tool in evaluating RV-pulmonary arterial coupling in COPD.

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan‐Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment‐naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44–68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow‐up time of 489 days (281–812 days). The 1‐, 2‐, and 3‐year mortality was 8% (95% CI, 6%–10%), 16% (95% CI, 13%–19%), and 21% (95% CI, 17%–25%), respectively. When stratified into low‐, intermediate‐, and high‐risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment‐naïve patients, initial combination therapy was associated with better 1‐year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19–0.95]; P =0.037). Conclusions Mortality in the intermediate‐ and high‐risk patients with PAH remains unacceptably high in the PHAR, suggesting the importance for early diagnosis, aggressive use of available therapies, and the need for better therapeutics.

Right ventricular (RV) function is a major contributor to the outcome of pulmonary arterial hypertension (PAH). Adult studies demonstrated that regional and global changes in RV deformation are prognostic in PAH using 3-dimensional echocardiography (3DE). However, regional and global dynamic changes in RV mechanics have not been described in pediatric PAH. We compared 3DE RV regional and global deformation between pediatric patients who had associated PAH with congenital heart disease (APAH-CHD), pediatric patients who had idiopathic PAH (IPAH), and normal controls, and evaluated the clinical outcomes.A total of 48 controls, 47 patients with APAH-CHD, and 45 patients with IPAH were evaluated. 3DE RV sequences were analyzed and post-processed to extract global and regional deformation (circumferential, longitudinal, and area strain). Statistical analyses compared the sub-groups on the basis of global and regional deformation, and outcome analysis was performed.Patients with PAH had significantl8y different global and regional deformation (p0.001) compared with controls. Patients with APAH-CHD and and those with IPAH significantly differed in global circumferential strain (p0.010), area strain (inlet septum, p = 0.041), and circumferential strain at the inlet septum (p0.019), apex free wall (p0.004), and inlet free wall (p0.004). Circumferential strain at the inlet free wall and circumferential, longitudinal, and area strain at the apex free wall were predictors of adverse events.RV regional and global strain differ between controls and pediatric patients with PAH. RV apical free-wall area strain provides insight into the mechanism of RV dysfunction in pediatric patients with PAH, with regional strain emerging as outcome predictors, suggesting that this novel measure may be considered as a future measure of RV function.

Rationale: Obesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations, and survival is not well understood. Objectives: To assess the effect of obesity on HRQoL, hospitalizations, and survival in patients with PAH. Methods: We performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed-effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 and emPHasis-10. We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status. Results: A total of 767 subjects were included (mean age of 57 years, 74% female, 33% overweight, and 40% with obesity), with median follow-up duration of 527 days. Overweight patients and patients with obesity had higher baseline emPHasis-10 scores (worse HRQoL), which persisted over time (P

FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion (FUTURE) 3 was a 24-week open-label, prospective, and randomized phase 3 study that assessed the pharmacokinetics of bosentan 2 mg/kg b.i.d. or t.i.d. in children with pulmonary arterial hypertension (PAH). We report findings from a post-hoc analysis that explored the prognostic value of echocardiographic changes during FUTURE 3 in relation to clinical outcomes observed during the 24-week core study and 48-week extension. Patients aged ≥3 months to n = 64) received oral doses of bosentan 2 mg/kg b.i.d. or t.i.d. (1:1) for 24 weeks, after which they were eligible to enter the extension with continued bosentan administration. Echocardiographic evaluations were performed at baseline, Week 12, and 24 of the core study via central reading, and analyzed post-hoc for correlation with clinical outcomes (time to PAH worsening, time to death, and vital status). Sixty-four patients were randomized in the core study [median (IQR) age 3.8 (1.7–7.8) years]; and 58 patients (90.6%) entered the 48-week extension. Most of the patients (68.8%) were receiving ≥1 PAH medication at baseline. Echocardiographic changes during the core study were small but with high variability. There were statistically significant associations at Week 24 between worsening of the parameters, systolic left ventricular eccentricity index (LVEIS) and E/A ratio mitral valve flow, and the outcomes of time to death and time to PAH worsening. Additional studies that utilize simple and reproducible echocardiographic assessments are needed to confirm these findings and subsequently identify potential treatment goals in pediatric PAH.

Background Elevated systemic afterload in patients with Fontan circulation may lead to impaired single ventricular function. Wave intensity analysis (WIA) enables evaluation of compression and expansion waves traveling through vasculature. We aimed to investigate the unfavorable wave propagation causing excessive afterload may be an important contributor to the overall single ventricle function and to the limited functional capacity in this patient population. Methods Patients with hypoplastic left heart syndrome (HLHS) (n = 25), single left ventricle (SLV) (n = 24), and normal controls (n = 10) underwent phase-contrast MRI based WIA analysis evaluated in the ascending aorta. Forward compression wave (FCW) representing dP/dt, backward compression wave (BCW) reflecting vascular stiffness, and forward decompression wave (FDW) representing LV relaxation were recorded and indexed to each other. Results FCW was lowest in HLHS patients (1098 mm5/s), and higher in the SLV group (1457 mm5/s), and controls (6457 mm5/s) (P Conclusions Patients with HLHS and SLV have unfavorable aortic WIA patterns with increased BCW/FCW ratio indicating increased systemic afterload due to retrograde compression waves. Reduced FCW and systolic MRI indices correlated with peak VO2 suggesting that abnormal systolic wave propagation may play a role in exercise intolerance for Fontan patients.

Pulmonary hypertension (PH), the syndrome of increased pressure in the pulmonary arteries, is associated with significant morbidity and mortality for affected children and is associated with a variety of potential underlying causes. Several pulmonary arterial hypertension-targeted therapies have become available to reduce pulmonary artery pressure and improve outcome, but there is still no cure for most patients. This review provides a description of select causes of PH encountered in pediatrics and an update on the most recent data pertaining to evaluation and management of children with PH. Available evidence for specific classes of PH-targeted therapies in pediatrics is discussed.

Background WHO Group 1 pulmonary arterial hypertension is a progressive and potentially fatal disease. Individuals living at higher altitude are exposed to lower barometric pressure and hypobaric hypoxemia. This may result in pulmonary vasoconstriction and contribute to disease progression. We sought to examine the relationship between living at moderately high altitude and pulmonary arterial hypertension characteristics. Methods Forty-two US centers participating in the Pulmonary Hypertension Association Registry enrolled patients who met the definition of WHO Group 1 pulmonary arterial hypertension. We utilized baseline data and patient questionnaire responses. Patients were divided into two groups: moderately high altitude residence (home ≥4000 ft) and low altitude residence (home

Flow through the proximal pulmonary arteries (PAs) of patients with repaired Tetralogy of Fallot (TOF) is known to be highly disordered and associated with significant regurgitation. The purpose of this study was to evaluate 4D-Flow MRI-derived viscous energy loss [Formula: see text])-as a result of non-efficient flow propagation, and relate this parameter to standard right ventricular (RV) size and function markers in patients with repaired TOF.Thirty-five patients with TOF and 14 controls underwent comprehensive 4D-Flow MRI evaluation for qualitative flow analysis and to calculate [Formula: see text] in the main and right pulmonary arteries. Sampled [Formula: see text] indices were correlated with the MRI-derived RV size and functional indices.All patients with TOF exhibited abnormal, supra-physiologic helical/vortical formations in the PAs. Patients with TOF had significantly increased peak systolic [Formula: see text] (8.0 vs 0.5 mW, p0.001), time-averaged [Formula: see text] (2.5 vs. 0.2 mW, p0.001), and peak systolic [Formula: see text] indexed to stroke volume (0.082 vs. 0.012 mW/mL, p0.001). [Formula: see text] indexed to stroke volume correlated with the RV end-diastolic volume (R = 0.68, p0.001), end-systolic volume (R = 0.62, p0.001), ejection fraction (R = -0.45, p = 0.002), and cardiac index (R = 0.45, p = 0.002). The mean estimated energy loss due to [Formula: see text] with regard to input RV mechanical power was 4.7%.This study demonstrates that patients with repaired TOF have highly abnormal flow conduction through the PAs which result into extensive viscous energy loss. This significant flow-mediated energy loss is associated with the RV volume and function, and might represent considerable loss of mechanical power generated by each cardiac cycle. Future studies are required to assess whether the abnormal flow conduction adds to the RV afterload and remodeling.• Abnormal flow patterns through proximal pulmonary arteries in patients with TOF are associated with excessive viscous energy loss. • Inefficient flow conduction is associated with the RV dilation and reduced function and might contribute to the RV adaptive remodeling.

Background Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH. Methods Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0-21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity. Results Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p Conclusions Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension. Impact Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology.There are few studies looking at the pathobiology of pulmonary hypertension only in children.The IGF axis is dysregulated in pediatric pulmonary arterial hypertension.IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension.IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.Fig. 1IGF1 AND IGFBP2 CONCENTRATION (NG/ML) IN PAH BIOBANK VERSUS CONTROLS.: a IGF1 concentration (ng/mL) in PAH Biobank versus asthmatic subjects. b IGFBP2 concentration (ng/mL) in PAH Biobank versus asthmatic subjects.Fig. 2ROC CURVE OF IGF1 AND IGFBP2 IN PAH BIOBANK VERSUS CONTROLS.: a ROC curve of IGF1 in PAH Biobank subjects versus controls. AUC 0.82. Cut point for IGF1 of 177 ng/mL gives a sensitivity of 73.9% and a specificity of 78.3%. b ROC curve of IGFBP2 in PAH Biobank subjects versus controls. AUC 0.80. Cut point for IGFBP2 of 185 ng/mL gives a sensitivity of 72.2% and a specificity of 80.4%.Fig. 3IGFBP2 CONCENTRATIONS IN PAH SUBJECTS BY MEDICATION COMBINATION.: a IGFBP2 concentration in PAH subjects on a PDE5 inhibitor, a PDE5 inhibitor and an ERA, a PDE5 inhibitor and IV/SQ PCA, or a combination of PDE5 inhibitor, ERA, and IV/SQ PCA. b IGFBP2 concentrations in PAH subjects on an IV/SQ PCA and any other therapy versus subject not on IV/SQ PCA and any other therapy.Fig. 4Kaplan-Meier curve showing time to death, transplant, or palliative shunt (Pott's shunt or atrial septostomy) dichotomized by the median IGFBP2 level.

BACKGROUND The age of patients with pulmonary arterial hypertension (PAH) has increased, with registries now reporting mean ages of 50 to 65 years old. Limited data exist on age-related differences in hemodynamic and functional assessments in PAH. METHODS Adults with PAH in the Pulmonary Hypertension Association Registry were divided into 3 groups (18–50, 51–65, and >65 years old). Analysis of variance and chi-square testing were used to assess for baseline differences. Linear regression was used to examine the association of age with continuous hemodynamic and functional variables. RESULTS A total of 769 patients with mean age of 56 ± 16 years were included. Older patients had more connective tissue disease–associated PAH and less drug-associated PAH. In linear regression models, each year of increased age was associated with shorter 6-minute walk distance (−3.37 meters; 95% CI, −3.97 to −2.76), lower mean pulmonary arterial pressure (−0.21 mm Hg; 95% CI, −0.27 to −0.15), and lower pulmonary vascular resistance (−0.06 Wood units; 95% CI, −0.09 to −0.04). Pulmonary arterial compliance, cardiac index, right ventricular stroke work index, and percent predicted 6-minute walk distance were unrelated to age; resistance-compliance time was negatively related to age (−3 milliseconds per year; 95% CI, −4 to −2). CONCLUSIONS Relative to their pulmonary vascular resistance, older patients have lower pulmonary artery compliance and worse right ventricular performance. Based on these findings, we suspect that age influences right ventricular loading conditions and the response of the right ventricle to increased afterload.

Idiopathic pulmonary arterial hypertension (PAH) is a severe disease associated with a 20% 5-year mortality, often due to right heart failure. Recent studies suggest that compensatory changes in right atrial (RA) function may precede other clinical and echocardiographic evidence of right ventricular dysfunction. No prior prospective study has evaluated the role of RA emptying pattern as a prognostic marker of adverse clinical events in pediatric PAH.To demonstrate whether RA fractional emptying indices will prospectively predict risk of adverse clinical outcomes in pediatric PAH patients.Single-center, prospective cohort analysis of 41 patients with idiopathic or heritable PAH and 1:1 age and sex-matched controls with normal echo and electrocardiogram. Right atrial area (RAA) was measured just prior to tricuspid valve opening (RAAmax), at electrical p wave (RAAp), and just after tricuspid valve closing (RAAmin). Right atrial conduit fraction percent (RA cF%) was defined as the percentage of total RAA change happening prior to the electrical p wave = (RAAmax - RAAp)/(RAAmax - RAAmin) ∗ 100. Clinical worsening was analyzed with a predefined composite adverse event outcome.RA measurements were technically feasible in all study participants. The PAH patients (median age 11.9 years) had decreased RA cF% compared with controls (P .0001), and PAH subjects with lower RA cF% demonstrated higher right ventricular systolic (R = -0.49, P = .019) and end-diastolic (R = -0.52, P = .012) pressure than those with higher RA cF%. Sixteen subjects had a clinical event. Right atrial cF% (hazard ratio = 0.09; P .001) was highly prognostic for risk of adverse clinical event with area under the curve = 0.90 on receiver operating characteristic curve analysis (median 3.2-year follow-up).Right atrial conduit phase emptying is significantly altered in pediatric PAH. Within the PAH population, decreased RA cF% was prognostic for risk of clinical worsening. The combination of accuracy and ease of measurement could make RA cF% a clinically useful, noninvasive biomarker of early right heart failure and risk of disease progression in pediatric PAH.

BACKGROUND: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models. METHODS: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models. RESULTS: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity. CONCLUSIONS: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.

The Fontan circulation is characterized as a nonpulsatile flow propagation without a pressure-generating ventricle. However, flow through the Fontan circulation still exhibits oscillatory waves as a result of pressure changes generated by the systemic single ventricle. Identification of discrete flow patterns through the Fontan circuit may be important to understand single ventricle performance. Ninety-seven patients with Fontan circulation underwent phase-contrast MRI of the right pulmonary artery, yielding subject-specific flow waveforms. Principal component (PC) analysis was performed on preprocessed flow waveforms. Principal components were then correlated with standard MRI indices of function, volume, and aortopulmonary collateral flow. The first principal component (PC) described systolic versus diastolic-dominant flow through the Fontan circulation, accounting for 31.3% of the variance in all waveforms. The first PC correlated with end-diastolic volume ( R = 0.34, P = 0.001), and end-systolic volume ( R = 0.30, P = 0.003), cardiac index ( R = 0.51, P < 0.001), and the amount of aortopulmonary collateral flow ( R = 0.25, P = 0.027)—lower ventricular volumes and a smaller volume of collateral flow—were associated with diastolic-dominant cavopulmonary flow. The second PC accounted for 19.5% of variance and described late diastolic acceleration versus deceleration and correlated with ejection fraction—diastolic deceleration was associated with higher ejection fraction. Principal components describing the diastolic flow variations in pulmonary arteries are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to preserved ventricular volume and function, respectively. NEW & NOTEWORTHY The exact physiological significance of flow oscillations of phasic and temporal flow variations in Fontan circulation is unknown. With the use of principal component analysis, we discovered that flow variations in the right pulmonary artery of Fontan patients are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to more ideal ventricular volume and systolic function, respectively.

Individuals with Down syndrome (DS) have an increased risk of developing pulmonary hypertension (PH). In this review, we explore the epidemiology and clinical characteristics of PH in the population with DS and examine genetic, molecular and clinical contributions to the condition. The presence of an additional copy of chromosome 21 (trisomy 21) increases the risk of developing PH in children with DS through many mechanisms, including increased hemodynamic stress in those with congenital heart disease, hypoxemia through impaired ventilation to perfusion matching secondary to developmental lung abnormalities, pulmonary hypoplasia from pulmonary vascular endothelial dysfunction, and an increase in pulmonary vascular resistance often related to pulmonary comorbidities. We review recent studies looking at novel biomarkers that may help diagnose, predict or monitor PH in the population with DS and examine current cardiopulmonary guidelines for monitoring children with DS. Finally, we review therapeutic interventions specific to PH in individuals with DS. Contemporary work has identified exciting mechanistic pathways including the upregulation of antiangiogenic factors and interferon activity, which may lead to additional biomarkers or therapeutic opportunities. Throughout the manuscript, we identify gaps in our knowledge of the condition as it relates to the population with DS and offer suggestions for future clinical, translational, and basic science research.

Adverse ventricle-ventricle interaction and resultant left ventricular (LV) dysfunction are a recognized pathophysiological component of disease progression in pulmonary arterial hypertension (PAH) and can be associated with electrical and mechanical dyssynchrony. The purpose of this study was to investigate the clinical and mechanistic implications of LV electromechanical dyssynchrony in children with PAH by using novel systolic stretch and diastolic relaxation discoordination indexes derived noninvasively from cardiac MRI (CMR). In children with PAH referred for CMR ( n = 64) and healthy controls ( n = 20), we calculated two novel markers of ventricular discoordination, systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF). SSF and DRF were evaluated with respect to 1) electrical dyssynchrony, 2) functional status, and 3) composite clinical outcomes. SSF was increased in patients with PAH compared with controls ( P = 0.004). There was no difference in DRF between PAH and control groups. There were no differences between groups in standard mechanical dyssynchrony and LV global circumferential strain. Increased SSF was associated with greater electrical dyssynchrony (QRS duration) as well as worse WHO functional class. SSF, DRF, mechanical dyssynchrony, and right ventricular (RV) volumes were prognostic for worse clinical outcomes. LV dyssynchrony indexes are altered in pediatric patients with PAH compared with controls in proportion with greater degrees of RV dilation. Patients with PAH with greater dyssynchrony have worse clinical outcomes. RV-induced increased LV electromechanical dyssynchrony therefore may be an important link in the causal pathway from PAH to clinically significant LV dysfunction. Since dyssynchrony could precede overt LV dysfunction, addition of ventricular synchrony analysis to CMR postprocessing protocols may be of clinical benefit. NEW & NOTEWORTHY We demonstrate that left ventricular discoordination indexes are altered in pediatric patients with pulmonary arterial hypertension compared with controls and pediatric patients with pulmonary arterial hypertension with greater dyssynchrony have worse clinical outcomes. Furthermore, there is evidence for the mechanism of right ventricular-induced left ventricular discoordination to include a combination of delayed early systolic electromechanical activation, late-systolic septal shift, and prolonged, postsystolic septal thickening.

Pediatric pulmonary arterial hypertension (PAH) is a rare but severe disease with no cure. In this review, we discuss an approach to the evaluation and management of a pediatric patient with suspected or confirmed PAH. Proceedings published from the 2018 World Symposium updated the definition of pulmonary hypertension to include all adults and children with mean pulmonary artery pressure > 20 mmHg. A classification scheme for patients with PAH associated with congenital heart disease is now also well recognized. Recent research and guidelines have described a series of risk stratification criteria as well as specific criteria for operability in children with unrepaired systemic-to-pulmonary shunt lesions. Although multiple medications have been used off-label, in 2017, bosentan became the first targeted PAH therapy approved for use in children. In recent years, advanced imaging and clinical monitoring have allowed improved risk stratification of PH patients. New therapies, approved in adults and used off-label in pediatric patients, have led to improved outcomes for affected children. However, no targeted pulmonary hypertension medications are approved for children

Aortopathy is a recognized comorbidity of Tetralogy of Fallot (TOF). Aortic flow in children with repaired TOF is abnormal despite normal aortic valve anatomy and early surgical repair that results in aortic size normalization. The purpose of this study was to investigate the flow hemodynamics inside the left ventricle (LV) of children with repaired TOF using 4D-Flow MRI derived vorticity. Vorticity is the spatial derivative of flow velocity and is sensitive to anatomic and geometric variations. Vorticity was calculated inside the LV of children with repaired TOF having normal aortic size (n = 14) and normal controls (n = 10) during systolic ejection phase. All subjects underwent comprehensive biventricular analysis including the MRI based feature-tracking based LV strain analysis and mechanical dyssynchrony. Right ventricular (RV) volumetric indices along with LV mechanical indices were correlated with LV vorticity. All TOF patients had supraphysiologic helical flow in the ascending aorta. The generated peak systolic vorticity integrated over the LV volume was elevated in TOF group compared to control (median: 1344 vs. 858 s−1, P

Background: In pulmonary arterial hypertension (PAH), right ventricular (RV) failure is the main cause of mortality. Non-invasive estimation of ventricular-vascular coupling ratio (VVCR), describing contractile response to afterload, could be a valuable tool for monitoring clinical course in children with PAH. This study aimed to test two hypotheses: VVCR by cardiac magnetic resonance (VVCRCMR) correlates with conventional VVCR by right heart catheterization (VVCRRHC) and both correlate with disease severity.Methods and results: Twenty-seven patients diagnosed with idiopathic and associated PAH without post-tricuspid shunt, who underwent RHC and CMR within 17 days at two specialized centers for pediatric PAH were retrospectively studied. Clinical functional status and hemodynamic data were collected. Median age at time of MRI was 14.3 years (IQR: 11.1-16.8), median PVRi 7.6 WU x m(2) (IQR: 4.1-12.2), median mPAP 40 mm Hg (IQR: 28-55) and median WHO-FC 2 (IQR: 2-3). VVCRCMR, defined as stroke volume/end-systolic volume ratio was compared to VVCRRHC by single-beat pressure method using correlation and Bland-Altman plots. VVCRCMR and VVCRRHC showed a strong correlation (r = 0.83, p Conclusions: Non-invasively measured VVCRCMR is feasible in pediatric PAH and comparable to invasively assessed VVCRRHC. Both correlate with functional and hemodynamic measures of disease severity. The role of VVCR assessed by CMR and RHC in clinical decision-making and follow-up in pediatric PAH warrants further clinical investigation. (C) 2019 Elsevier B.V. All rights reserved.

OBJECTIVE: To describe the safety and tolerability of treatment with ambrisentan and tadalafil in pediatric pulmonary hypertension (PH). STUDY DESIGN: This retrospective observational two center study included subjects(≤18 years of age)with PH receiving combination therapy with ambrisentan and tadalafil. Prior to initiating this therapy,many patients were on other therapies for PH. At baseline,patients either received no therapy or monotherapy with a phosphodiesterase 5 inhibitor(PDE5i) or endothelin receptor antagonist(ERA)(Group A),switched from a different PDE5i and ERA(Group B),or were on prostanoid therapy with or without a PDE5i and/or ERA(Group C and D). Demographics,symptoms, and adverse effects were collected. Pre and post values for exercise capacity,hemodynamics and biomarkers were compared. RESULTS: There were 43 subjects(26F, 17M) ages 4-17.5years (median 9.3) with World Symposium of PH group 1,3 and 5. Significant improvements were seen in change scores at follow-up in the entire sample and Group A for 6-minute walk distance: +37.0(6.5–71.0)[P=.022], mean pulmonary artery pressure:−6.0(−14.0 – −3.5)[P=.002], pulmonary vascular resistance: −1.7 (−6.2 – −1.0)[P=.003], NT-proBNP −32.9(−148.9– −6.7)[P=.025]. WHO functional class improved in 39.5% and was unchanged in 53.5%;PH risk scores improved in 16%; were unchanged in 56%; and declined in 14%. Three patients discontinued therapy (2 headaches,1 peripheral edema). Seven patients were hospitalized for worsening disease (2/7 had a Potts shunt placed,2/7 had an atrial septostomy). There were no deaths or lung transplantation. CONCLUSIONS: Combination therapy with ambrisentan and tadalafil was well-tolerated,with an acceptable safety profile in a select group of children. This therapy was associated with improved exercise capacity and hemodynamics in children who were treatment naïve or on monotherapy with a PH medication prior to the initiation of ambrisentan and tadalafil. Based on these early data,further study of combination therapy in pediatric PH is warranted.

Persons with Down syndrome (DS) have an increased reported incidence of pulmonary hypertension (PH). A majority of those with PH have associations with congenital heart disease (CHD) or persistent pulmonary hypertension of the newborn (PPHN); however, there are likely multifactorial contributions that include respiratory comorbidities. PH appears to be most commonly identified early in life, although respiratory challenges may contribute to a later diagnosis or even a recurrence of previously resolved PH in this population. Currently there are few large-scale, prospective, lifetime cohort studies detailing the impact PH has on the population with DS. This review will attempt to summarize the epidemiology and characteristics of PH in this population. This article will additionally review current known and probable risk factors for developing PH, review pathophysiologic mechanisms of disease in the population with DS, and evaluate current screening and management recommendations while suggesting areas for additional or ongoing clinical, translational, and basic science research.

Background Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH. Methods and Results Serum endostatin was measured in cross‐sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH‐CHD, N=185). Outcomes, assessed by regression and Kaplan‐Meier analysis, included hemodynamics, change in endostatin over time, and transplant‐free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH‐CHD. In APAH‐CHD, endostatin was associated with a shorter 6‐minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant‐free survival. Addition of endostatin to an NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells. Conclusions Endostatin is associated with disease severity, disease improvement, and worse survival in APAH‐CHD. Endostatin with NT‐proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH‐CHD.

AimsVentricular–vascular coupling, the ratio between the right ventricle’s contractile state (Ees) and its afterload (Ea), may be a useful metric in the management of paediatric pulmonary arterial hypertension (PAH). In this study we assess the prognostic capacity of the ventricular–vascular coupling ratio (Ees/Ea) derived using right ventricular (RV) pressure alone in children with PAH.MethodsOne hundred and thirty paediatric patients who were diagnosed with PAH via right heart catheterisation were retrospectively reviewed over a 10-year period. Maximum RV isovolumic pressure and end-systolic pressure were estimated using two single-beat methods from Takeuchi et al (Ees/Ea_(Takeuchi)) and from Kind et al (Ees/Ea_(Kind)) and used with an estimate of end-systolic pressure to compute ventricular–vascular coupling from pressure alone. Patients were identified as either idiopathic/hereditary PAH or associated PAH (IPAH/HPAH and APAH, respectively). Haemodynamic data, clinical functional class and clinical worsening outcomes—separated into soft (mild) and hard (severe) event categories—were assessed. Adverse soft events included functional class worsening, syncopal event, hospitalisation due to a proportional hazard-related event and haemoptysis. Hard events included death, transplantation, initiation of prostanoid therapy and hospitalisation for atrial septostomy and Pott’s shunt. Cox proportional hazard modelling was used to assess whether Ees/Ea was predictive of time-to-event.ResultsIn patients with IPAH/HPAH, Ees/Ea_(Kind) and Ees/Ea_(Takeuchi) were both independently associated with time to hard event (p=0.003 and p=0.001, respectively) and when adjusted for indexed pulmonary vascular resistance (p=0.032 and p=0.013, respectively). Neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to soft event. In patients with APAH, neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to hard event or soft event.ConclusionsEes/Ea derived from pressure alone is a strong independent predictor of adverse outcome and could be a potential powerful prognostic tool for paediatric PAH.

Objective The reversed Potts shunt is an increasingly applied mode of surgical palliation of severe pulmonary hypertension (PH). However, the long-term flow hemodynamic effect of the Potts shunt physiology and desirable long-term hemodynamic end-points are not defined. The purpose of this descriptive study was to analyze a series of pediatric patients who underwent surgical Potts shunt as a part of end-stage PH palliation using 4D-Flow MRI to 1) quantitate the flow through the anastomosis, 2) correlate the shunting pattern with phases of cardiac cycle and PH comorbidities, and 3) describe chronologic changes in shunting pattern. Methods This was a two-center study evaluating four patients seen by the Pulmonary Hypertension Clinic at Children’s Hospital Colorado who were evaluated and selected to undergo surgical reverse Potts shunt at Washington University School of Medicine and were serially followed using comprehensive imaging including cardiac MRI and 4D-Flow MRI. Results Post procedure each child underwent two 4D-Flow MRI evaluations. Pulmonary pressure offload was evident in all patients as demonstrated by positive systolic right-to-left flow across the Potts shunt. All patients experienced some degree of the flow reversal which occurs primarily in diastole. Interventricular dyssynchrony further contributed to flow reversal across the Potts shunt. Lastly, systemic and pulmonary blood mixing in the descending aorta results in secondary helical flow persisting throughout the diastole. Conclusions 4D-Flow MRI demonstrates that children who have undergone a Potts shunt for severe PH can experience shunt flow reversal. Cumulatively this left-to-right pulmonary shunt adds to RV volume overload. We speculate that a valved conduit may decrease the left to right shunting and improve overall cardiac output.