PAH-targeted Therapy Research Articles

Towards a Better Prognosis in Patients with Systemic Sclerosis-Related Pulmonary Arterial Hypertension: Recent Developments and Perspectives.

Precapillary pulmonary hypertension (PH) is a significant complication of systemic sclerosis (SSc). It represents one of the leading causes of morbidity and mortality, correlating with a significantly dismal prognosis and quality of life. Despite advancements in the management of patients with pulmonary arterial hypertension associated with SSc (SSc-PAH), no significant improvement has been reported in survival of patients with precapillary SSc-PH associated with extensive lung parenchyma disease. International expert consensus and guidelines for the management of PH recommend annual screening of SSc patients for early detection of pre-capillary PH. The implementation of screening algorithms capable of identifying patients with a high likelihood of developing PH could help limit unnecessary right-heart catheterization procedures and prevent significant delay in diagnosis. Furthermore, early initiation of up-front combination targeted therapy in patients with PAH has shown increase in survival rates, indicating that timely and aggressive medical therapy is key for stabilizing and even improving functional class, hemodynamic parameters and 6 min walking distance (6MWD) in this population. Further research is warranted into the benefit of PAH-targeted therapies in patients with PH associated with lung disease. Lastly, we discuss the potential role of immunosuppression using biologic agents in the therapeutic management of precapillary PH in SSc patients.

Contemporary survival outcomes of congenital systemic-to-pulmonary shunt in children with borderline pulmonary vascular resistant index compared to Eisenmenger syndrome

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) is a complication that occurs after unrepaired significant systemic-to-pulmonary shunt. Treatment options for PAH-CHD-predominantly left-to-right (L-R) shunt in children with borderline-high pulmonary vascular resistant index (PVRi) have been debated. We aimed to assess the treatment and survival of children with PAH-CHD-predominantly L-R shunt with borderline to high PVRi, using Eisenmenger syndrome (ES) for comparison. In 1995–2021, a total of 142 patients with ES and 192 children with PAH-CHD-predominantly L-R shunt were eligible for our analysis. The PVRi in ES patients was 26.7 ± 16.8 WU m2. Most patients (91%) received PAH-targeted therapy. Of the 192 children with PAH-CHD-predominantly L-R shunt, the baseline PVRi was 9.2 ± 5.8 WU m2. A total of 64 patients (33.3%) had borderline PVRi (4–8 WU m2) and 98 patients (51%) had high PVRi (> 8 WU m2). Most patients (88.5%) responded to acute pulmonary vasodilatory testing and underwent repair, with 158 undergoing defect closure and 12 having fenestrated closure. A treat-and-repair strategy was used in 33 children (17.1%). The 10- and 15-year survival rates for patients with ES were 79.3% and 72.4%, respectively, which was significantly inferior to children with borderline PVRi [97.3% and 87.8% (p = 0.02)]; and high PVRi [91.6% and 89.5% (p = 0.06)], respectively. The survival rate of children receiving treat-and-repair was slightly higher than that of ES (p = 0.16). The independent mortality risk in children with PAH-CHD-predominantly L-R shunt was persistent PAH following the defect correction (adjusted hazard ratio 5.8, 95% CI 1.7–19.9, p = 0.005).Trial registration: TCTR20200420004.

A Single Center Experience of Pulmonary Arterial Hypertension Management in Korea: A 25-Year Comparative Analysis Following the Introduction of Targeted Therapy.

The transformation of pulmonary arterial hypertension (PAH) treatment in Korea, ushered by targeted therapy's advent, prompted our analysis of baseline attributes, treatment trends, and survival shifts within our single-center registry. We examined 230 patients (72.6% female, mean age 40.6±17.4 years) diagnosed and/or treated between 1980 and 2021 in our PAH clinic. Given targeted therapy's introduction and active use since 2007, we compared diagnostic classification, demographics, and treatment patterns at that juncture. Survival analysis encompassed PAH types and the overall population. For historical survival comparison, 50 non-registry patients were retrospectively added, and age-sex matching enabled pooled analysis. Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) constituted the largest subset (43.0%), trailed by connective tissue disease-associated PAH (CTD-PAH, 29.6%) and idiopathic PAH (IPAH, 19.1%). Post-2007, CTD-PAH proportions surged, notably with an elevated initiation rate of targeted therapy (95.4%). Overall survival rates at 1, 5, and 10 years stood at 91.3%, 77.4%, and 65.8%, respectively, with CHD-PAH exhibiting superior survival to idiopathic or CTD-PAH. Age-sex matching analysis indicated survival disparities between those starting immediate targeted therapy vs. conservative treatment upon diagnosis, especially driven by IPAH. In the post-introduction of the targeted therapy era, patients with PAH promptly started treatment right away, and higher survival rates of patients who started initial PAH-targeted therapy were demonstrated. The transition towards early treatment initiation might have likely contributed to the elevated survival rates observed in Korea's PAH patient cohort.

Pulmonary Hypertension With Interstitial Pneumonia: Initial Treatment Effectiveness and Severity in a Japan Registry

BackgroundRecent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group. ObjectivesThe authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema. MethodsWe categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders. ResultsAmong 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis. ConclusionsThis study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541)

Contribution of pressure and flow changes to resistance reduction after pulmonary arterial hypertension treatment: a meta-analysis of 3898 patients.

Pulmonary arterial hypertension (PAH)-targeted therapies exert significant haemodynamic changes; however, systematic synthesis is currently lacking. We searched PubMed, CENTRAL and Web of Science for studies evaluating mean pulmonary artery pressure (mPAP), cardiac index/cardiac output (CI/CO) and pulmonary vascular resistance (PVR) of PAH-targeted therapies either in monotherapy or combinations as assessed by right heart catheterisation in treatment-naïve PAH patients. We performed a random-effects meta-analysis with meta-regression. We included 68 studies (90 treatment groups) with 3898 patients (age 47.4±13.2 years, 74% women). In studies with small PVR reduction (<4 WU), CI/CO increase (R2=62%) and not mPAP reduction (R2=24%) was decisive for the PVR reduction (p<0.001 and p=0.36, respectively, in the multivariable meta-regression model); however, in studies with large PVR reduction (>4 WU), both CI/CO increase (R2=72%) and mPAP reduction (R2=35%) contributed significantly to the PVR reduction (p<0.001 and p=0.01, respectively). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral+prostanoid intravenous/subcutaneous combination therapy (mean difference -50.0%, 95% CI -60.8- -39.2%), compared to oral combination therapy (-41.7%, -47.6- -35.8%), prostanoid i.v./s.c. monotherapy (-31.8%, -37.6- -25.9%) and oral monotherapy (-21.6%, -25.4- -17.8%). Changes in haemodynamic parameters were significantly associated with changes in functional capacity of patients with PAH as expressed by the 6-min walking distance. Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable haemodynamic improvement in treatment-naïve PAH patients and may unmask the contribution of mPAP reduction to the overall PVR reduction in addition to the increase in CO.

Sarcoidosis-Associated Pulmonary Hypertension

Sarcoidosis is characterized by non-necrotizing granulomatous aggregations affecting a range of organs, with thoracic structures involved in 90% to 95% of cases. This granulomatous disease can impact the pulmonary vasculature via different mechanisms resulting in sarcoidosis-associated pulmonary hypertension (SAPH). These include postcapillary disease (left heart disease), immune-mediated granulomatous vasculopathy, hypoxemia, thromboembolism, pulmonary vascular compression and/or stenosis by mediastinal lymph nodes/fibrosis, or sarcoidosis-related portal hypertension. SAPH is a serious complication, especially in those with end-stage lung disease. A thorough evaluation is crucial to delineate the predominant mechanism of PH in the affected individual. The management of SAPH is complex and necessitates a personalized, multifaceted approach, targeting the specific mechanisms and underlying pathologies. Such patients are best served at specialized Pulmonary Hypertension and Sarcoidosis Centers. A notable phenotype within SAPH is the “pulmonary arteriopathy” group, characterized by milder parenchymal disease and a favorable response to PAH-targeted therapy, whereas patients with active granulomatous inflammation are likely to respond to immunosuppression. Several PAH therapies have been used to treat SAPH, however, clear direction on the use of PAH therapies in SAPH is still lacking. Patients receiving pulmonary vasodilators should be carefully monitored for potential deterioration in gas exchange or development of pulmonary edema, which could suggest underlying left heart disease or pulmonary veno-occlusive disease. Timely referral for lung transplant evaluation is crucial for those with SAPH and severe parenchymal lung disease, ensuring a comprehensive and patient-centered care approach. Much work remains to be done to understand the exact pathogenesis of SAPH, as well as to develop therapies that clearly improve outcomes for these patients.

The Association Between Non-Clinically Apparent Liver Fibrosis and Pulmonary Arterial Hypertension in Hispanic Patients.

Pulmonary arterial hypertension (PAH) is a deadly cardiopulmonary disease with multi-organ involvement including impaired liver function. Liver dysfunction in PAH is poorly understood but significantly associated with morbidity and mortality. Hispanics have a significantly higher prevalence of non-alcoholic fatty liver disease (NAFLD) and evidence of more advanced disease in comparison to other ethnic groups. The clinical impact of NAFLD in Hispanic PAH patients is unknown. We aimed to investigate the impact of a validated scoring system, non-alcoholic fatty liver disease fibrosis score (NFS), to predict the degree of liver fibrosis in a Hispanic PAH population and its relationship to hemodynamics, functional class, and outcomes. A retrospective review of all treatment-naive Hispanic patients with group I World Health Organization (WHO) pulmonary hypertension (PH) at a single academic center between February 2016 and March 2021 was performed. Patients with history of substance or alcohol abuse, non-group I WHO PH, pre-existent liver disease, chronic kidney disease, atrial fibrillation, thyroid disease, and warfarin use were excluded from the study. The diagnosis of group I WHO PH was determined by cardiac catheterization after the exclusion of other etiologies. NFS was calculated for each patient and correlated with functional capacity, hemodynamics, N-terminal-pro-B-type natriuretic peptide (NT-proBNP), and survival. A total of 96 Hispanic patients were included in our study. The median age of patients in our cohort was 49 years (interquartile range: 15) and 69% of our cohort were females. Higher NFSs indicating advanced hepatic fibrosis (F3-F4) were found to correlate with elevated right-sided cardiac filling pressures (r = 0.27, P = 0.03), elevated levels of NT-proBNP (r = 0.32, P = 0.01), lower 6-minute walk distance (6MWD) (r = -0.49, P = 0.001), lower functional capacity (World Health Organization functional class, WHO-FC, r = -0.35, P = 0.051), a higher prevalence of diabetes (21.1% versus 51.9%, P = 0.001), a higher prevalence of risk factors for metabolic syndrome (81.5% versus 65.0%, P = 0.035), and worse 5-year survival rates. In Hispanic patients with PAH, NFSs correlate with the degree of right-sided pressure overload. In addition, advanced NFSs were independently associated with lower 5-year survival rates and added prognostic information to other established risk parameters in PAH. This study suggests that screening for liver disease in this vulnerable patient population can aid in earlier detection leading to discussion of lifestyle modifications and possible escalation of PAH-targeted therapies, thus leading to potential improvement in survival rates.

Epidemiology and management of patients with pulmonary arterial hypertension associated with congenital heart disease: data from the hellenic pulmonary hypertension registry (HOPE)

Abstract Background Pulmonary arterial hypertension (PAH) is a common complication among adult patients with congenital heart disease (CHD). Since clinical trials on PAH-CHD are scarce, registry data are required to shed light on the epidemiology and management of this subgroup. Purpose To present "real-world" data about the epidemiology, management and long-term course of PAH-CHD from the Hellenic Pulmonary Hypertension Registry (HOPE). Methods The HOPE registry was launched in early 2015 and enrols patients from all pulmonary hypertension subgroups in Greece. This analysis focuses on PAH-CHD. Results In total, 85 PAH-CHD patients of whom 50 women (59%) have been enrolled from 8 centers between 2015 and 2022. A follow-up visit was available in 39 patients (45.8%). Median age at first visit was 37 (24, 60) years. About three quarters of patients had a pre-tricuspid (n=32, 37.6%) or a post-tricuspid shunt (n=30, 35.2%), with a quarter of patients having a complex CHD (n=21, 24.7%). Eisenmenger physiology was present in 31 patients (36.4%). The most common comorbidities at baseline were obesity (n=14, 16%), thyroid disease (n=12, 14%) and atrial fibrillation (n=12, 14%). About two thirds of patients were mildly symptomatic at baseline (NYHA I/II, n=55, 64.7%) and remained so at follow-up (n=25/39, 63.7%) with a median time of last available visit at follow-up of 1484 days (4.1 years). According to the three strata ESC risk stratification score, half of patients were at intermediate risk at baseline, while more than half of patients were at low risk for 1-year mortality at follow up (Figure 1A). More than half of patients received PAH monotherapy at baseline (n=46, 54%), with one fifth not receiving any PAH-targeted therapy (n=18, 21.2%). At 4.1 years, half of patients were on combination therapy (n=20/39, 51.3%) (Figure 1B). During a median follow up time of 2547 days (7 years), 17 deaths were reported (0.01 deaths/ patient year) (Figure 2A). 1-, 3- and 5- year survival rates were 96.4% (92.4%-100%), 88.9% (82.3%-96%), and 88.9% (82.3%-96%), respectively. Survival was better among low-risk patients at baseline, compared to moderate and high-risk ones (Figure 2B). Conclusion In this national cohort of ACHD PAH there was a tendency towards combination therapy at follow-up which might be the cause for reduced mortality risk. The three strata ESC risk stratification score may be a useful tool to risk assess these patients for long-term survival.Risk stratification and pharmacotherapyOveral and risk-estimated mortality

Hemodynamic changes with pulmonary arterial hypertension targeted therapies: a meta-analysis of 3898 treatment-naive patients

Abstract Background Pulmonary arterial hypertension (PAH)-targeted therapies exert significant hemodynamic changes. We aimed to systematically synthesize these effects and explore the pulmonary pressure and flow changes in relation to the resistance changes. Methods We systematically searched PubMed, CENTRAL, and Web of Science for studies evaluating the hemodynamic effects (mean pulmonary artery pressure [mPAP], cardiac index/output [CI/CO], pulmonary vascular resistance [PVR]) of PAH-targeted therapies (comprising endothelin receptor antagonists [ERA], phosphodiesterase type 5 inhibitors [PDE5i], prostanoids [either i.v./s.c. or p.o./inh], riociguat, and selexipag) either in monotherapy or combinations as assessed by right heart catheterization (RHC) in treatment-naïve PAH patients. We performed a random-effects meta-analysis and used meta-regression to evaluate the contribution of mPAP % reduction and CI/CO % increase on the PVR % reduction across different treatment groups. Results We included 68 studies comprising 90 treatment groups and 4276 patients (age 47.3±13.2, 74% women). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral + prostanoid i.v./s.c. combination therapy (mean difference [MD] -50.0%, 95% confidence interval [CI] -60.8%; -39.2%), compared to oral combination therapy (MD -41.7%, 95% CI -47.6%; -35.8%), prostanoid i.v./s.c. monotherapy (MD -31.8%, 95% CI -37.6%; -25.9%), and oral monotherapy (MD -21.6%, 95% CI -25.4%; -17.8%) (Figure 1). The contribution of mPAP % reduction and of CI/CO % increase to the PVR % reduction was equally significant in all treatment groups (Figure 2). In the oral combination therapy group CI/CO % increase had superior contribution over mPAP % reduction (R2 90% vs R2 0%), but this difference was driven by an outlier study with n = 8 patients and after the exclusion of the outlier, the contribution of mPAP % reduction and of CI/CO % increase to the PVR % reduction was equally significant also in the oral combination group. The same results applied in a sensitivity analysis including only studies with idiopathic/heritable/drugs-induced/connective tissue disease-associated PAH patients. Conclusion Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable hemodynamic improvement in treatment-naïve PAH patients. The contribution of mPAP and CI/CO % changes to the overall PVR % reduction is equally significant.Figure 1Figure 2

Invasive Hemodynamic and Vasoreactivity Testing with Inhaled Iloprost in Children with Pulmonary Arterial Hypertension Associated with Congenital Heart Defects

Objective: Invasive hemodynamic evaluation and acute vasoreactivity testing are recommended in the diagnosis of pulmonary arterial hypertension (PAH), but their clinical role in children with PAH associated with congenital heart defects (CHD) is unclear. This study aims to investigate acute hemodynamic responses to inhaled iloprost, and its role in prognosis in children with PAH-CHD. Methods: A retrospective analysis was conducted on 83 pediatric patients with PAH-CHD in whom invasive hemodynamics were evaluated before and after a single inhaled dose of iloprost at a single center between 2010 and 2022. Details of the CHD corrective operation, medical treatment, and outcome for each patient were obtained via medical records or telephone contact. A composite endpoint of all-cause death, admission for worsening heart failure during follow-up, and event-free survival was defined, and risk factors associated with this composite endpoint were analyzed. Results: The patient age was (11.3 ± 4.6) years, and 60 (72.3%) were female. Fifty-nine (71.1%) patients were diagnosed with Eisenmenger syndrome. After iloprost inhalation, mean pulmonary artery pressure decreased from (78.2 ± 11.5) to (72.3 ± 13.2) mmHg (P &lt; 0.001), and pulmonary vascular resistance index (PVRI) decreased from (18.0 ± 7.9) to (14.5 ± 8.1) WU·m2 (P &lt; 0.001). A total of 38 (45.8%) patients had a positive response, defined as a PVRI decrease &gt;25% with stable systemic pressure. Thirty-seven (44.6%) patients underwent a corrective CHD operation at a median of 24 d after hemodynamic evaluation. Nine patients died, and 15 met the composite endpoint during a follow-up period of 5.4 (3.8, 8.8) years. Five-year event-free survival estimates were 96.7% (95% confidence interval: 90.3%–100%) in patients with a positive response, and 82.8% (95% confidence interval: 71.7%–94.5%) in patients with a non-positive response (log-rank P = 0.012). A positive PVRI response and higher pulmonary arterial oxygen saturation after iloprost inhalation, lower baseline brain natriuretic peptide, and PAH-targeted therapy at follow-up were significantly associated with a favorable clinical outcome. A positive acute vasoreactivity testing response and PAH-targeted therapy at follow-up were independent predictors of outcome in multivariate Cox analysis. Conclusions: Acute inhalation of iloprost can lead to a significant decrease in hemodynamic parameters. Responsiveness to inhaled iloprost is associated with better outcomes and can be a valuable predictor of outcomes.

Pulmonary vasodilators and exercise in Fontan circulation: a systematic review and meta-analysis

ObjectiveIn Fontan circulation, pulmonary arterial hypertension (PAH)-targeted therapies could improve the patients’ exercise capacity. This study aimed to investigate the effects of PAH agents on different exercise parameters in stable...

Pulmonary Arterial Hypertension in the Elderly: Peculiar Features and Challenges for a Proper Phenotyping Approach.

(1) Introduction. Although pulmonary arterial hypertension (PAH) usually affects young people with a low cardiovascular risk profile, progressive epidemiologic changes have been providing a codified phenotype of elderly subjects with PAH and increased risk predictors for left heart disease. We therefore conducted a systematic review to describe the current knowledge and characteristics of elderly individuals with PAH and further insights concerning their prognostic outcomes and therapeutic response. (2) Methods. A search was conducted in PubMed, Embase, and Cochrane Library for publications evaluating the epidemiology, diagnostic work-up, and treatment of PAH in elderly subjects. (3) Among the 74 publications initially retrieved, 16 full-text articles were selected for the present systematic review. Compared to their younger counterparts, elderly individuals with PAH showed greater clinical deterioration, reduced exercise capacity, and worse prognostic outcomes, as well as less response to PAH-targeted therapy and higher rates of PAH drug discontinuation. (4) Conclusions. Demographic changes over time contributed to define a peculiar PAH phenotype in elderly patients, with an increased burden of cardiovascular comorbidities and distinctive features compared to young patients. Further investigations are needed in order to better clarify the nosologic criteria, and management in this subset population.

Evolution and optimization of clinical trial endpoints and design in pulmonary arterial hypertension.

Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its N-terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.

Prognosis in Hispanic patient population with pulmonary arterial hypertension: An application of common risk stratification models.

Pulmonary arterial hypertension (PAH) is a cardiovascular disease with high mortality rate. Current guidelines propose initiation and escalation of PAH-targeted treatment based on a goal-directed approach targeting hemodynamic, functional, and biochemical variables. This approach has been successfully validated in large Caucasian cohorts. However, given the low number of Hispanic patients enrolled in large PAH trials and registries, it is unknown if the same prognostic tools can be applied tothis patient population. We analyzed a single-center outpatient cohort that consisted of 135 Hispanic patients diagnosed with PAH. Baseline characteristics werecalculated based on COMPERA, COMPERA 2.0 and REVEAL 2.0 risk scores before the initiation of PAH-targeted therapies. The survival rateat 1 year after diagnosis was 88% for the entire cohort. The three established risk scores to predict PAH outcomes yielded similar results with reasonable discrimination of mortality in the different risk strata (all p < 0.001). Hispanic patients with PAH have a high mortality rate. Our analysis suggests that guideline proposed risk assessment at baseline yields important prognostic information in this patient population.

10-year survival of pulmonary arterial hypertension associated with connective tissue disease: insights from a multicenter PAH registry.

To report the 10-year survival rate and prognostic factors of pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) patients, to compare treatment and survival between patients enrolled before and after 2015, and to validate the discrimination of the recommended 4-strata model in predicting 10-year survival at follow-up in Chinese CTD-PAH patients. This study was derived from a Chinese national multicentre prospective registry study from 2009 to 2019. Medical records were collected at baseline and follow-up, including PAH-targeted therapy and binary therapy (both CTD and PAH-targeted therapy). A total of 266 CTD-PAH patients were enrolled and the 10-year survival rate was 59.9% (median follow-up time: 4.85 years). Underlying CTD (SSc), baseline 6-min walking distance and SaO2 were independent risk factors for 10-year survival. The proportion of patients receiving PAH-targeted combination therapy increased from 10.1% (2009-2014)-26.5% (2015-2019) and that of binary therapy increased from 14.8% to 35%. The 1-year survival rate increased from 89.8% (2009-2014)-93.9%, and the 3-year survival rate increased from 80.1% (2009-2014)-86.5% (both p > 0.05). The 4-strata strategy performed well in predicting 10-year survival at follow-up (C-index = 0.742). The 10-year survival rate of CTD-PAH patients was reported for the first time. The 10-year prognosis was poor, but there was a tendency for more standardized treatment and better survival in patients enrolled after 2015. The recommended 4-strata model at follow-up can effectively predict 10-year survival in CTD-PAH patients.

Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry

The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p=0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

Differences in right ventricular function and response to targeted therapy between patients with IPAH and PAH-CHD.

Background and aims: Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disorder characterized by elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Right heart failure is a life-threatening complication of PAH and predicts a poor prognosis. PAH associated with congenital heart disease (PAH-CHD) and idiopathic PAH (IPAH) are two prevalent PAH subtypes in China. In this section, we set out to explore baseline right ventricular (RV) function and its response to targeted agents between IPAH and PAH-CHD. Methods and results: Consecutive patients diagnosed with IPAH or PAH-CHD by right heart catheterization (RHC) in the Second Xiangya Hospital from November 2011 to June 2020 were included. All patients received PAH-targeted therapy and the RV function was assessed by echocardiography at baseline and during follow-up. A total of 303 patients (age, 36.23 ± 13.10years; women, 213 (70.3%); mean PAP [mPAP], 63.54 ± 16.12mmHg; PVR, 14.74 ± 7.61WU) with IPAH (n = 121) or PAH-CHD (n = 182) were included in this study. Compared with PAH-CHD, patients with IPAH had worse baseline RV function. As of the latest follow-up, forty-nine patients with IPAH and six patients with PAH-CHD died. Kaplan-Meier analyses showed better survival in PAH-CHD versus IPAH. After PAH-targeted therapy, patients with IPAH had less improvement in 6MWD, World Health Organization functional class, and RV functional parameters compared with patients with PAH-CHD. Conclusion: Compared with patients with PAH-CHD, patients with IPAH had worse baseline RV function, unfavourable prognosis, and inadequate response to targeted treatment.

Pulmonary veno-occlusive disease in Sjogren's syndrome: a case report

BackgroundPulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) belongs to Group 1 pulmonary hypertension. Pulmonary veno-occlusive disease (PVOD), which is characterized by venous system aberrations, has been previously reported in CTD-PAH; however, it has rarely been observed in Sjogren’s syndrome (SS).Case presentationOur 28-year-old female patient was admitted to the hospital with recurrent shortness of breath even after minimal physical activity. Her chest high-resolution CT scan demonstrated pulmonary artery dilatation and bilateral ground-glass nodules. A subsequent right heart catheterization confirmed pulmonary hypertension because her mean pulmonary arterial pressure was 62 mmHg. Our inquisitive genomic assessment identified a novel EIF2AK4 mutation at c.1021 C > T (p. Gln341*), the dominant causal gene of PVOD. Histological examination demonstrated stenosis and occlusions in the pulmonary veins. Because she presented with features such as dry eyes and Raynaud's phenomenon, we performed a biopsy on the labial salivary gland, which confirmed SS. Her treatment regimen included PAH-targeted therapies (tadalafil and macitentan) in combination with hydroxychloroquine. Although she was hospitalized several times due to acute exacerbation of PAH, her disease progression was under control, and she did not demonstrate any signs of pulmonary edema even after a three-year treatment period.ConclusionHere, we report the case of an SS-PAH patient with PVOD who carried a novel biallelic EIF2AK4 mutation, and PAH-targeted therapies were well tolerated by our patient.

“Treat-Repair-Treat”: Management of Left Main Coronary Compression by a Pulmonary Artery Aneurysm in a Patient with Atrial Septal Defect and Significant Pulmonary Hypertension

Left main coronary compression syndrome (LMCS) may complicate pulmonary artery aneurysms (PAA), usually developed in the context of pulmonary arterial hypertension (PAH). We report the case of a 51-year-old female patient with an atrial septal defect (unsuitable for device closure) complicated by a PAA generating a 90% left main stenosis. The significant PAH held us back from immediate surgery. After specific dual PAH-targeted therapy (sildenafil and bosentan), the atrial septal defect could be closed with a unidirectional valved patch; the PAA-induced LMCS was treated by reductive arterioplasty. The postoperative course was uneventful. Follow-up showed clinical improvement, but PAH treatment was still needed. After three months, coronary angiography showed only an insignificant residual left main stenosis, proving that reductive pulmonary arterioplasty was effective in treating LMCS. Any PAA requires further evaluation for LMCS, a dangerous but treatable complication. The “treat-repair-treat” strategy and shunt-closure with a unidirectional valved patch can both improve surgical prospects of LMCS with shunt-related PAH.

AD-9308 ameliorates the impacts of 4-HNE on the progress of pulmonary arterial hypertension in aldehyde dehydrogenase 2*1*2 knock-in mice

Abstract Endothelial dysfunctions play a critical role on the development of pulmonary arterial hypertension (PAH). It has been reported that the one-year mortality rate is still up to 15% even with PAH-targeted therapy, implying that there may be untargeted pathways. 4-hydroxynenonal (4-HNE), an unsaturated aldehyde, is highly induced in the lungs of PAH animals and its serum levels were also reported to be higher in PAH patients. 4-HNE is metabolized by mitochondrial aldehyde dehydrogenase (ALDH2), which is dysfunctional in near 40% of East Asian people. Currently, the impacts of 4-HNE on endothelial dysfunctions in the development of PAH are unclear. In terms of translational medicine, we proposed that modulation of 4-HNE level may alleviate the progress of PAH patients with ALDH2 deficiency. We found that 4-HNE alone was not sufficient to induce pulmonary artery endothelial cell (PAEC) functional changes, including proliferation, migration and tube formation, whereas their effects emerge from the depletion of ALDH2. We further mimicked human ALDH2 functional deficiency by using daidzin (DZN), an inhibitor which is able to block the substrate binding site of ALDH2. ALDH2 functional inhibition alone did not induce any PAEC functional change, while an add-on of 4-HNE impaired PAEC functions. In addition, 4-HNE significantly reduced eNOS activity with combined DZN treatment. Consistent with the mechanism of ALDH2 activity-mediated angiogensis, ALDH2 enhancers Alda-1 and AD-5591 completely reverse the anti-angiogenic effects of 4-HNE in the presence of DZN. To further confirm whether ALDH2 functional deficiency impact on PAH development in mammals, heterozygous ALDH2*1/*2 transgenic and wild-type mice were subjected to chronic hypoxia to induce PAH. ALDH2*1/*2 transgenic mice had similar right ventricular systolic pressure (RVSP) as wild-type mice. However, after exposure to chronic hypoxia, ALDH2*1/*2 transgenic mice indeed developed a significantly higher RVSP than that in wild-type mice. Furthermore, we demonstrated that 4-HNE expression was profoundly enhanced in ALDH2*1/*2 transgenic mice by chronic hypoxia-induced PAH with pulmonary artery smooth muscle cell hyperplasia. More importantly, we found that AD-9308, an enhancer of ALDH2 significantly decreased hypoxia-induced RVSP elevation in heterozygous ALDH2*1/*2 transgenic mice. Taken together, our data demonstrate that 4-HNE and ALDH2 functional deficiency potentially contribute to PAH development and worsening, and that ALDH2 enhancers may be promising as a PAH adjunct therapy, particularly for patients with ALDH2 nonfunctional alleles. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and Technology, Taiwan