Outcomes In Pulmonary Arterial Hypertension Research Articles

Impact of Initial Therapeutic Strategy on Long-Term Outcomes in Pulmonary Arterial Hypertension: An Analysis of the PHSANZ Registry

<h3>Purpose</h3> The relationship between initial treatment strategy and survival in pulmonary arterial hypertension (PAH) is uncertain, although early combination therapy is proposed by current guidelines for majority of patients. <h3>Methods</h3> Data were extracted from the Pulmonary Hypertension Society of Australia and New Zealand registry for all patients with a diagnosis with idiopathic/heritable/toxin-induced (I/H/D-PAH) with survival, treatment response and medication data. Patients were divided into prevalent (diagnosed < 2011), early incident (diagnosed 2011-2015) and recent incident (diagnosed 2016-2019) cohort. Early combination therapy was defined as the use of 2 or more drugs within 3 months of treatment initiation. <h3>Results</h3> A total of 489 patients diagnosed between 2006 and 2019 were included with 318 (65%) started on monotherapy, 156 (32%) on early double combination therapy and 13 (3%) on early triple therapy. All patients on triple therapy were on parenteral prostacyclin, as well as 20 (13%) patients of double therapy and 2 (0.6%) receiving monotherapy. Rates of early combination therapy (double or triple) were 20%, 28% and 59% across the 3 treatment eras. In the entire population, there was no significant differences in transplant-free survival according to upfront treatment strategy (log rank test p=0.66). After adjustment for baseline risk according to REVEAL 2.0 score, HR for monotherapy compared to early combination therapy (2 or 3 agents) was 1.11 [0.79-1.62]. With analysis restricted to incident cases only, the adjusted HRs for monotherapy compared to early combination were 1.57 [0.86-2.84] for the period 2011-2015, and 0.78 [0.25-2.40] for period 2016-2019. Change in 6MWD was higher in the early combination group versus monotherapy group (51±86m vs 74±113m, p=0.017). <h3>Conclusion</h3> In a real-world registry where early combination therapy consisted mainly of dual oral agents, a survival benefit over monotherapy was not observed. Further studies are needed to determine impact of specific drug combinations (such as inclusion of parenteral prostacyclin) on long term outcomes.

"Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension." Catherine E. Simpson, Jenny Y. Chen, Rachel L. Damico, et al. Eur Respir J 2020; 55: 1901761.

"Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension." Catherine E. Simpson, Jenny Y. Chen, Rachel L. Damico, et al. Eur Respir J 2020; 55: 1901761.

Treatment with neurohormonal inhibitors and prognostic outcome in pulmonary arterial hypertension with risk factors for left heart disease.

BACKGROUNDDespite major advances in pharmacologic treatment, patients with pulmonary arterial hypertension (PAH) still have a considerably reduced life expectancy. In this context, chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH, thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target.AIMTo evaluate the application and prognostic effect of neurohormonal inhibitors (NEUi) in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease.METHODSWe analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1, 2005 to October 31, 2018. Patients on beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi non-recipients.RESULTSComplete data were available for 57 PAH subjects: 27 of those (47.4%) were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients. NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients. Additionally, NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients (56.7% vs 25.9%, log-rank P = 0.020).CONCLUSIONThe above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival. Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.

Impact of Initial Therapeutic Strategy on Long-Term Outcomes in Pulmonary Arterial Hypertension: An Analysis of the PHSANZ Registry

The relationship between initial treatment strategy and survival in pulmonary arterial hypertension (PAH) is uncertain, although early combination therapy is proposed by current guidelines for majority of patients.

Clinical Relevance of Right Atrial Functional Response to Treatment in Pulmonary Arterial Hypertension

Background: Right atrial (RA) function has emerged as an important determinant of outcome in pulmonary arterial hypertension (PAH). However, studies exploring RA function after initiation of specific pulmonary vascular treatment and its association with outcome in patients with incident PAH are lacking.Methods: RA peak longitudinal strain (PLS), passive strain (PS), and peak active contraction strain (PACS) were retrospectively assessed in 56 treatment-naïve patients with PAH at baseline and during follow-up after initiation of specific monotherapy or combination therapy. Patients were grouped according to their individual RA functional response to treatment, based on change from baseline (Δ): worsened (first Δ-tertile), stable (second Δ-tertile), and improved (third Δ-tertile). The Spearman's rho correlation and linear regression analysis were used to determine associations. Time to clinical worsening (defined as deterioration of functional class or 6-min walking distance, disease-related hospital admission, or death) was measured from the follow-up assessment. The association of RA functional treatment response with time to clinical worsening was assessed using the Kaplan–Meier and the Cox regression analyses.Results: Median (interquartile range) time to echocardiographic follow-up was 11 (9–12) months. Of the 56 patients, 37 patients (66%) received specific dual or triple combination therapy. Δ RA PLS during follow-up was significantly associated with changes in key hemodynamic and echocardiographic parameters. The change of pulmonary vascular resistance, right ventricular (RV) end-systolic area, and global longitudinal strain were independently associated with Δ RA PLS. The median time to clinical worsening after echocardiographic follow-up was 6 (2–14) months [17 events (30%)]. In the multivariate Cox regression analysis, worsening of RA PLS was significantly associated with clinical deterioration (hazard ratio: 4.87; 95% CI: 1.26–18.76; p = 0.022). Patients with worsened RA PLS had a significantly poorer prognosis than those with stable or improved RA PLS (log-rank p = 0.012). By contrast, PS and PACS did not yield significant prognostic information.Conclusion: Treatment-naïve patients with PAH may show different RA functional response patterns to PAH therapy. These functional patterns are significantly associated with clinically relevant outcome measures. Improvements of RA function are driven by reductions of afterload, RV remodeling, and RV dysfunction.

Non-Invasive Risk Prediction Based on Right Ventricular Function in Patients with Pulmonary Arterial Hypertension.

Background: Right ventricular dysfunction is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to identify echocardiographic right heart parameters associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients. Methods and Results: In 254 PAH patients we analyzed functional status, laboratory results, and echocardiographic parameters. We included these parameters to estimate all-cause death or lung transplantation using Cox regression models. The analyses included a conventional model using guideline-recommended variables and an extended echocardiographic model. Based on the final model a 12-point risk score was derived, indicating the association with the primary outcome within five years. During a median follow-up time of 4.2 years 74 patients died or underwent lung transplantation. The conventional model resulted in a C-Index of 0.539, whereas the extended echocardiographic model improved the discrimination (C-index 0.639, p-value 0.017). Ultimately, the newly developed risk score included WHO functional class, 6-min walking distance, N-terminal brain natriuretic peptide concentrations, pericardial effusion, right atrial area, tricuspid annular plane systolic excursion, and fractional area change. Conclusion: Integrating right heart function assessed by echocardiography improves prediction of death or lung transplantation in PAH patients. Independent validation of this finding is warranted.

Atrioventricular plane displacement and regional contribution to stroke volume to predict outcome in pulmonary arterial hypertension

Abstract Background Patients with pulmonary arterial hypertension (PAH) exhibit high mortality, partially related to right heart failure. Right ventricular (RV) volumes and ejection fraction (EF) can be measured accurately with cardiac magnetic resonance (CMR), but EF is a crude measure of cardiac function. Additional methods for risk assessment and prognosis are of value. Stroke volume (SV) is generated by longitudinal, lateral and septal myocardial contraction. Longitudinal contribution to SV (SVlong%) generated from the atrioventricular displacement (AVPD) is the major contributor to SV in both the left ventricle (LV) and RV. AVPD in both sides and LVSVlong% are lower in patients with PAH compared to controls. However, it is unknown if altered AVPD or regional contributions to SV are prognostic in patients with PAH. The aim of this study was therefore to evaluate if AVPD, longitudinal, lateral or septal contribution to LVSV and RVSV are associated with death or lung transplantation in patients with PAH. Purpose To evaluate if biventricular AVPD, and regional contributions to SV are associated with outcome in patients with PAH. Methods Seventy-one patients with PAH and 20 sex and age-matched healthy controls underwent CMR. Endocardial and epicardial borders and RV insertion points were defined in end diastole and end systole in cine short-axis stacks to compute biventricular volumes, SVlat% and SVsept%. Eight atrioventricular points were defined in end diastole and end systole in 2-, 3- and 4-chamber cine long-axis views, for computation of AVPD and SVlong%. Cut-off values for survival analysis were defined as above or below mean ± 2 standard deviations from the healthy controls. Outcome was defined as death or lung-transplantation. Results Median follow-up time was 3.6 [IQR 3.7] years. AVPD, SVlong%, SVlat% in both ventricles and SVsept% were altered in PAH compared to controls. Transplantation-free survival was lower with values below cut-off for LV-AVPD (hazard ratio (HR)=2.1, 95% CI: 1.2–3.9, p=0.02) and RV-AVPD (HR=9.8, 95% CI: 4.6–21.1, p=0.005) (fig 1). In cox regression analysis, decreased LV-AVPD and RV-AVPD inferred lower transplantation-free survival (LV: HR=1.16 per mm decrease, p=0.007; RV: HR=1.11 per mm decrease, p=0.01) (table 1). LVEF, RVEF, LV-SVlong%, RV-SVlong%, LV-SVlat%, RV-SVlat% or SVsept% did not affect outcome (table 1). Conclusions Decreased left and right AVDP were associated with decreased transplantation-free survival in patients with PAH. There were no associations between ejection fraction, longitudinal, lateral or septal contribution to stroke volume. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Skåne University Hospital, Region of Skåne Southern Healthcare Region of Sweden

Impact of routine screening on detection, severity and outcome of pulmonary arterial hypertension in systemic sclerosis

Abstract Introduction It has been reported that up to 20% of systemic sclerosis (SSc) patients can be asymptomatic at the time of pulmonary arterial hypertension (PAH) diagnosis. The significant prevalence rate, lack of symptoms and high morbidity and mortality from SSc-PAH as well as the potential benefit from early intervention with the more widely available therapeutic options provide a strong rationale for active screening programs. The DETECT algorithm was developed in 2013 from a large prospective and multicentre study in SSc patients with higher risk of PAH. The objective of this study was to examine the impact of a screening program on the early detection of SSc-PAH. We looked at serial patients diagnosed with SSc associated PAH (SSC-PAH) in a large national pulmonary hypertension referral centre. Patients and methods All newly diagnosed adult patients with SSc-PAH prospectively enrolled in a large national pulmonary hypertension referral centre. The current study included newly diagnosed patients between January 2006 and January 2018. Results Three-hundred and five patients were diagnosed with SSc-PAH in our centre between 2006 and 2018. Of these, 164 patients were diagnosed before 2013 (January 2006 - December 2012) and 141 after 2013 (January 2013 - January 2018). Demographics were similar at presentation between the two groups. The non-invasive (WHO-FC, 6-MWD and NT-proBNP) and haemodynamic measurements (RAP, CI and SvO2) were used to calculate the ESC guidelines risk score. It was noted that higher proportion of patients in the post-2013 were in the higher risk categories than the pre 213 group (84.4% vs. 78%) but this was not found to be statistically significant (p value 0.356). There was no statistically significant difference in survival between the two groups (Post 2013 group, 1-, 3- year and 5-year survival was 87.9%, 60.4% and 52.1%, respectively and pre-2013 group 1-, 3- year and 5-year survival 89.6%, 65.2% and 49%, respectively) with a log rank p value of 0.869. Applying Cox regression analysis of proportional hazard and adjusting for ESC risk score at baseline, predicted survival was not found to be statistically different between the two groups. The ESC risk category at baseline was a highly significant predictor of survival as expected. Conclusion There remains a strong rationale for active screening for PAH in SSc patients which has a poor prognosis despite advances in therapeutic strategies. However, the current screening programme does not seem to have resulted in significantly earlier detection in this cohort. It would be important to analyse other patient populations in order to understand the impact of screening programmes. The current screening programs limitations may explain why we have not been able to detect more patients in the lower risk categories. Further development of these programs in order to overcome their shortfalls is direly needed. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Health ServiceRoyal Free NHS Trust Survival analysis

Plasma ADAMTS13 and von Willebrand factor in diagnosis and prediction of prognosis in pulmonary arterial hypertension.

To improve outcome in pulmonary arterial hypertension, earlier diagnosis and better prognostic assessments are required. We aimed to investigate the diagnostic and prognostic potential of plasma proteins related to pathways recognized in pulmonary arterial hypertension including coagulation, inflammation, and metabolism. Forty-two proteins were analysed with proximity extension assay from plasma of 20 healthy controls and 150 patients, including (pulmonary arterial hypertension, n = 48, whereof 33 also during early treatment follow-ups); chronic thromboembolic pulmonary hypertension (CTEPH, n = 20); pulmonary hypertension (PH) due to heart failure (HF) with preserved ejection fraction (HFpEF-PH, n = 31); PH due to HF with reduced ejection fraction (HFrEF-PH, n = 36); and HF without PH (Dyspnoea/HF-non-PH, n = 15). Patients’ haemodynamics were assessed by right heart catheterization. Plasma ADAMTS13 in incident pulmonary arterial hypertension was lower compared to the healthy controls (p = 0.055), as well as CTEPH (p < 0.0001), HFrEF-PH (p < 0.0001), HFrEF-PH (p < 0.0001), and Dyspnoea/HF-non-PH (p < 0.0001). Adjusted for age and sex, ADAMTS13 discriminated pulmonary arterial hypertension from the other disease groups with an AUC of 0.91 (sensitivity = 87.5%, and specificity = 78.4%). Higher plasma von Willebrand factor was associated with worse survival (log-rank p = 0.0029), and a higher mortality rate (adjusted hazard ratio 1.002, 95% confidence interval 1–1.004; p = 0.041). Adjusted for age, sex, and combined with the ESC/ERS risk score, von Willebrand factor predicted mortality (median follow-up 3.6 years) in pulmonary arterial hypertension with an AUC of 0.94 (sensitivity = 81.3%, and specificity=93.8%). ADAMTS13 may be a promising biomarker for early detection of PAH and von Willebrand factor as a candidate prognostic biomarker. The putative additional value of von Willebrand factor to the European multiparametric risk assessment strategy remains to be elucidated.

Is pulmonary vascular resistance index better than pulmonary vascular resistance in predicting outcomes in pulmonary arterial hypertension?

In contrast to pulmonary vascular resistance (PVR), PVR index (PVRI) accounts for variations in body habitus. We tested the association of PVRI compared to PVR with clinical outcomes in lean and obese (BMI ≥30 kg/m2) patients with pulmonary arterial hypertension (PAH). This retrospective study included adult patients with PAH who underwent right heart catheterization at Cleveland Clinic between February 1992 and November 2019. We included 644 patients (mean age, 53 ± 16 years, and 74 % females). PAH was idiopathic or heritable in 44% of patients. Cardiac output increased (p <0.0001), while PVR decreased (p <0.0001) with increasing body weight. Both PVR and PVRI were associated with markers of disease severity, with more pronounced association for PVRI. Both PVR and PVRI were risk factors for first PAH hospitalization, mortality and mortality or lung transplant in the whole cohort and the group of patients with BMI < 30 kg/m2. However, PVRI (HR (95% CI): 1.06 (1.02 -1.11)), but not PVR (HR (95% CI): 1.03 (0.99-1.07)), was a risk factor for first PAH hospitalization in obese patients. In the obese group, neither PVR nor PVRI were risk factors for mortality. PVRI appears to have a stronger association than PVR with disease severity markers in PAH; however, both PVR and PVRI were similarly associated with hospitalizations and survival in the overall cohort. We found no strong evidence to recommend a change from PVR to PVRI in the definition of PAH.

Innovative therapeutic strategy using prostaglandin I2 agonist (ONO1301) combined with nano drug delivery system for pulmonary arterial hypertension

Clinical outcomes of pulmonary arterial hypertension (PAH) may be improved using targeted delivery system. We investigated the efficacy of ONO1301 (prostacyclin agonist) nanospheres (ONONS) in Sugen5416/hypoxia rat models of PAH. The rats were injected with saline (control) or ONONS (n = 10, each) on days 21 and 28, respectively. Hepatocyte growth factor (HGF)-expressing fibroblasts and inflammatory cytokines were measured. Cardiac performance was assessed and targeted delivery was monitored in vivo, using Texas red-labeled nanoparticles. Compared with control, HGF-expressing fibroblasts and HGF expression levels were significantly higher in the ONONS group, while the levels of interleukin-6, interleukin-1β, transforming growth factor-β, and platelet-derived growth factor were lower. Histological assessment revealed significant amelioration of the percent medial wall thickness in pulmonary vasculature of rats in the ONONS group. Rats in the ONONS group showed decreased proliferating cell nuclear antigen-positive smooth muscle cells and improved right ventricle pressure/left ventricle pressure. No difference was seen in the accumulation of Texas red-labeled nanoparticles in the brain, heart, liver, and spleen between PAH and normal rats. However, a significant area of nanoparticles was detected in the lungs of PAH rats. ONONS effectively ameliorated PAH, with selective delivery to the damaged lung.

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension.

Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops, the gold standard for measuring RV function, are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multibeat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP - BSP), augmentation index as ESP - BSP/pulse pressure, pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure, and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP - BSP. ESP - BSP also significantly correlated with multibeat Ees/Ea (Spearman's ρ: -0.518, P < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP - BSP obtained by routine right heart catheterization significantly correlated with a noninvasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; ρ: -0.376, P < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH.

Better Outcomes in Pulmonary Arterial Hypertension After Repair of Congenital Heart Disease, Compared With Idiopathic Pulmonary Arterial Hypertension

BackgroundPulmonary vascular changes in postoperative pulmonary artery hypertension (PAH) are similar to those seen in idiopathic PAH. Data are sparse on direct comparative midterm outcomes for these 2 high-risk populations. MethodsPatients with idiopathic or postoperative PAH referred to a large tertiary hospital between June 2005 and July 2019 were retrospectively evaluated. ResultsA total of 364 consecutive patients were studied, including 201 postoperative PAH patients and 163 patients with idiopathic PAH, with a median age of 18.7 (interquartile range 10.0, 31.5) and 7.3 (IQR: 2.9, 18.3) years, respectively. PAH-specific drugs were used in 77.7% of patients; 31.4% received combination therapy. Patients with idiopathic PAH had a shorter 6-mintue walk distance, lower percutaneous oxygen saturation, and higher B-type natriuretic peptide levels than those with postoperative PAH at diagnosis (all P < 0.001), During a median follow-up time of 3.4 (interquartile range: 2.1, 5.8) years, 56 patients (15.4%) died, and one underwent bilateral lung transplantation. Patients with postoperative PAH had better survival than those with idiopathic PAH, according to age (hazard ratio [HR] 0.128, 95% confidence interval [CI]: 0.07-0.22, P < 0.0001); Kaplan–Meier survival estimates at 5 years for idiopathic and postoperative PAH patients were 74.3% and 92.6%, respectively. Patients in New York Heart Association functional class III–IV had an over 4-fold increased risk of death (HR 4.85, 95% CI: 2.61-9.00, P < 0.0001). Patients < 18 years of age at idiopathic PAH diagnosis had a worse survival compared to adult patients (HR 6.90, 95% CI: 4.19-15.56, P = 0.040). ConclusionsPostoperative-PAH patients had better midterm survival compared to patients with idiopathic PAH. Mortality was significant in both PAH groups, reinforcing the need for early diagnosis and optimal individualized management to improve outcomes.

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Abstract 14287: Iron Deficiency is Associated With More Severe Pulmonary Vascular Disease in Pulmonary Hypertension Due to Chronic Lung Disease

Background: Iron deficiency promotes pulmonary vascular remodeling in pre-clinical models, and is associated with worse outcomes in pulmonary arterial hypertension. However, the consequences of iron deficiency in patients with pulmonary hypertension due to chronic lung disease (Group 3 PH) are unexplored. Methods: We studied 122 consecutive Group 3 PH patients from the University of Minnesota Pulmonary Hypertension Repository. Serum soluble transferrin receptor (sTR) levels quantified iron deficiency. We evaluated the relationship between iron deficiency and pulmonary vascular disease, right ventricular (RV) function, exercise capacity, and survival. Results: The iron deficient group (&lt;4.8mg/L sTR) had significantly higher mean pulmonary arterial pressure (40±9 mmHg, n=59 vs. 44±13 mmHg, n=61; p =.02) and lower pulmonary arterial compliance (2.2±1.2 mL/mmHg, n=52 vs. 1.7±0.8 mL/mmHg, n=55; p =.01), but there was no difference in pulmonary vascular resistance. Moreover, there were trends for higher right atrial pressure (7±4 mmHg, n=58 vs. 9±6 mmHg, n=61; p =0.08) in iron deficient patients. However, iron deficiency did not significantly alter RV function by echocardiography, 6-minute walk distance, or survival. Conclusions: Iron deficiency in Group 3 PH is associated with worse pulmonary vascular disease. This suggests iron deficiency could contribute to pulmonary vascular disease in Group 3 PH, and future studies are needed to determine if iron replacement could be a therapy for this deadly type of PH.

Right ventricular area strain from 3-dimensional echocardiography: Mechanistic insight of right ventricular dysfunction in pediatric pulmonary hypertension

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 (p < 0.001) compared with controls. Patients with APAH-CHD and and those with IPAH significantly differed in global circumferential strain (p < 0.010), area strain (inlet septum, p = 0.041), and circumferential strain at the inlet septum (p < 0.019), apex free wall (p < 0.004), and inlet free wall (p < 0.004). 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.

Clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension secondary to congenital portosystemic shunts.

The aim of this retrospective study was to investigate the clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension (PAH) secondary to congenital portosystemic shunts (CPSS). Thirty-three pediatric patients diagnosed in our institution with CPSS between 2012 and 2019 were enrolled in this study. The patients were divided into PAH and non-PAH groups. The PAH group included 15 patients who presented with unexplained PAH when CPSS was diagnosed. Two patients with microangiopathic hemolytic anemia died of right heart failure shortly after diagnosis. One patient received a liver transplant at the age of 4.3 years and showed a mild decrease in pulmonary artery pressure (PAP) 4 years after the operation. Seven patients underwent one-stage shunt closure at a median age of 2.8 years (1.4-13 years). Follow-up examinations, from 1.6 to 4.1 years after intervention, showed marked reduction of PAP in one patient and stabilization of PAH in six others. However, in one patient who underwent two-stage shunt closure, a marked increase in PAP was noted after partial ligation of the shunt. The remaining four patients received only pulmonary vasodilator therapy, and one of them died of right heart failure 12 years after the PAH diagnosis. The non-PAH group included 18 patients without evidence of PAH upon CPSS diagnosis. Shunt closure was carried out in eight of these patients, but one patient subsequently developed PAH after the resolution of hepatopulmonary syndrome.Conclusion: CPSS may be a more likely cause of unexplained PAH in pediatric patients than previously thought. Shunt closure or liver transplantation may prevent the progression of PAH, or even improve it for the majority of CPSS patients.

Effects of macitentan and tadalafil monotherapy or their combination on the right ventricle and plasma metabolites in pulmonary hypertensive rats.

Pulmonary arterial hypertension is a severe respiratory disease characterized by pulmonary artery remodeling. RV dysfunction and dysregulated circulating metabolomics are associated with adverse outcomes in pulmonary arterial hypertension. We investigated effects of tadalafil and macitentan alone or in combination on the RV and plasma metabolomics in SuHx and PAB models. For SuHx model, rats were injected with SU5416 and exposed to hypoxia for three weeks and then were returned to normoxia and treated with either tadalafil (10 mg/kg in chow) or macitentan (10 mg/kg in chow) or their combination (both 10 mg/kg in chow) for two weeks. For PAB model, rats were subjected to either sham or PAB surgery for three weeks and treated with above-mentioned drugs from week 1 to week 3. Following terminal echocardiographic and hemodynamic measurements, tissue samples were collected for metabolomic, histological and gene expression analysis. Both SuHx and PAB rats developed RV remodeling/dysfunction with severe and mild plasma metabolomic alterations, respectively. In SuHx rats, tadalafil and macitentan alone or in combination improved RV remodeling/function with the effects of macitentan and combination therapy being superior to tadalafil. All therapies similarly attenuated SuHx-induced changes in plasma metabolomics. In PAB rats, only macitentan improved RV remodeling/function, while only tadalafil attenuated PAB-induced changes in plasma metabolomics.

Long-term outcomes in pulmonary arterial hypertension by functional class: a meta-analysis of randomized controlled trials and observational registries.

Limited data about the long-term prognosis and response to therapy in pulmonary arterial hypertension patients with World Health Organization functional class I/II symptoms are available. PubMed and Embase were searched for publications of observational registries and randomized, controlled trials in pulmonary arterial hypertension patients published between January 2001 and January 2018. Eligible registries enrolled pulmonary arterial hypertension patients ≥18 years, N > 30, and reported survival by functional class. Randomized, controlled trial inclusion criteria were pulmonary arterial hypertension patients ≥18 years, ≥6 months of treatment, and morbidity, mortality, or time to worsening as end points reported by functional class. The primary outcomes were survival for registries and clinical event rates for randomized, controlled trials. Separate random effects models were calculated for registries and randomized, controlled trials. Four randomized, controlled trials (n = 2482) and 10 registries (n = 6580) were included. Registries enrolled 9%–47% functional class I/II patients (the vast majority being functional class II) with various pulmonary arterial hypertension etiologies. Survival rates for functional class I/II patients at one, two, and three years were 93% (95% confidence interval (CI): 91%–95%), 86% (95% CI: 82%–89%), and 78% (95% CI: 73%–83%), respectively. The hazard ratio for the treatment effect in randomized, controlled trials overall was 0.61 (95% CI: 0.51–0.74) and 0.60 (95% CI: 0.44–0.82) for functional class I/II patients and 0.62 (95% CI: 0.49–0.78) for functional class III/IV. The calculated risk of death of 22% within three years for functional class I/II patients underlines the need for careful assessment and optimal treatment of patients with functional class I/II disease. The randomized, controlled trial analysis demonstrates that current medical therapies have a beneficial treatment effect in this population.

Heart rate monitoring improves clinical assessment during 6-min walk.

Right ventricular (RV) function is a predictor of outcomes in pulmonary arterial hypertension (PAH). The 6-min walk test (6MWT) is likely an indirect measure of RV function during exercise, but changes in absolute walk distance can also be influenced by factors like effort and musculoskeletal disease. Paired 6MWT with continuous electrocardiogram monitoring was performed in stable PAH patients, patients adding PAH therapies, and healthy controls. Heart rate expenditure (HRE) was calculated (integrating pulse during 6MWT) and then divided by walk distance (HRE/d). We also evaluated changes in peak heart rate, time above age-adjusted maximum predicted heart rate, and heart rate at 6 min. HRE/d was compared to invasive hemodynamic measures in patients who had right heart catheterization performed within seven days, WHO functional class assessment, and Emphasis 10 questionnaire. We measured two 6MWT in 15 stable PAH patients, 13 treatment intensification patients, and 8 healthy controls. HRE/d was reproducible in the stable PAH group (median difference, −0.79%), while it decreased (median difference, 23%, p = 0.0001) after adding vasodilator therapy. In 11 patients with right heart catheterization, HRE/d correlated strongly with stroke volume, r = −0.72, p = 0.01. Peak heart rate decreased after adding vasodilator therapy. HRE/d also correlated with WHO functional class and Emphasis 10 score. Continuous heart rate monitoring during 6MWT provides valuable physiologic data accounting for effort. HRE/d appears to enhance test reproducibility in stable patients while detecting change after adding therapy as compared to walk distance alone.