Etiology Of Pulmonary Arterial Hypertension Research Articles

Comprehensive risk assessment in patients with pulmonary arterial hypertension referred for lung transplantation: a single-center experience

Abstract Background Current guidelines recommend risk stratification to optimize the timing to refer patients with pulmonary arterial hypertension (PAH) for lung transplantation (LT). However, the optimal timing for referral may vary by country. It is unknown whether risk stratification could be helpful to predict the post-referral outcome in Japan where the waiting period is about 3 years. Purpose We aimed to investigate the predictive value of risk stratification at the LT referral time, and to provide a decision-making tool to refer patients for LT. Methods We performed a retrospective cohort study of consecutive PAH patients referred for LT from May 2014 to December 2021. Risk status was assessed by the ESC/ERS three-strata and four-strata model (Figure 1). For assessment, functional class, six-minute walk distance, brain natriuretic peptide, the ratio of TAPSE to PASP, mean right atrial pressure and cardiac index were used as variables. In the exploratory analysis, the intermediate risk group by the three-strata model was further divided into two groups based on the median proportion of low-risk variables (modified risk assessment): low-intermediate or high-intermediate risk. The primary outcome was all-cause mortality after referral. Results 52 patients were enrolled [median age 30.5 (22.0-40.0) years, 83% idiopathic/heritable PAH]. During a median follow-up period of 2.5 (1.8-3.4) years, 9 patients died, and 13 patients underwent LT. By the three-strata model, 15, 36, and 1 patients were classified as low-, intermediate- and high risk (Figure 2a). There was no significant difference in survival between low- and intermediate risk. By the four-strata model, 33, 16, and 3 patients were classified as low-intermediate-, high-intermediate and high risk (Figure 2b). The four-strata model identified high-risk patients with survival rates of 33% at 1 year, whereas did not discriminate survival between low-intermediate and high-intermediate risk. By the modified risk assessment, 15, 28, 8 and 1 patients were classified as low-, low-intermediate, high-intermediate and high risk (Figure 2c). Patients at high-intermediate risk or higher had significantly worse survival (P<0.001); survival rates at 3 years were 92%, 80% and 34% in the low-, low-intermediate, and high-intermediate or high-risk group, respectively. In Cox regression analysis, high-intermediate or high risk by the modified risk assessment was significantly associated with the primary outcome adjusted for age, sex and PAH etiologies (HR, 6.284; 95% CI, 1.743-22.662; p=0.005). Conclusion The prognosis of high-risk group by the four-strata model was too poor to survive the waiting period. Whereas, the modified risk assessment could discriminate patients who could continue medical therapy or should be referred for LT. Risk stratification could help clinicians to make decisions to refer patients for LT. Further work is needed to refine the assessment tool in the context of LT referral.

Regional Variation in Pulmonary Arterial Hypertension in the United States: The Pulmonary Hypertension Association Registry.

Rationale: Pulmonary arterial hypertension (PAH) is a heterogeneous disease within a complex diagnostic and treatment environment. Other complex heart and lung diseases have substantial regional variation in characteristics and outcomes; however, this has not been previously described in PAH. Objectives: To identify baseline differences between U.S. census regions in the characteristics and outcomes for participants in the Pulmonary Hypertension Association Registry (PHAR). Methods: Adults with PAH were divided into regional groups (Northeast, South, Midwest, and West), and baseline differences between census regions were presented. Kaplan-Meier survival analyses and Cox proportional hazards were used to estimate the association between region and mortality in unadjusted and adjusted models. Results: Substantial differences by census regions were seen in age, race, ethnicity, marital status, employment, insurance payor breakdown, active smoking, and current alcohol use. Differences were also seen in PAH etiology and baseline 6-minute walk distance test results. Treatment characteristics varied by census region, and mortality appeared to be lower in PHAR participants in the West (hazard ratio, 0.60; 95% confidence interval, 0.43-0.83, P = 0.005). This difference was not readily explained by differences in demographic characteristics, PAH etiology, baseline severity, baseline medication regimen, or disease prevalence. Conclusions: The present study suggests significant regional variation among participants at accredited pulmonary vascular disease centers in multiple baseline characteristics and mortality. This variation may have implications for clinical research planning and represent an important focus for further study to better understand whether there are remediable care aspects that can be addressed in the pursuit of providing equitable care in the United States.

Differential expression spectrum and targeted gene prediction of tRNA-derived small RNAs in idiopathic pulmonary arterial hypertension.

Background: Idiopathic pulmonary arterial hypertension (PAH) is a potentially fatal pulmonary vascular disease with an extremely poor natural course. The limitations of current treatment and the unclear etiology and pathogenesis of idiopathic PAH require new targets and avenues of exploration involved in the pathogenesis of PAH. tRNA-derived small RNAs (tsRNAs), a new type of small non-coding RNAs, have a significant part in the progress of diverse diseases. However, the potential functions behind tsRNAs in idiopathic PAH remain unknown. Methods: Small RNA microarray was implemented on three pairs of plasma of idiopathic PAH patients and healthy controls to investigate and compare tsRNAs expression profiles. Validation samples were used for real-time polymerase chain reaction (Real-time PCR) to verify several dysregulated tsRNAs. Bioinformatic analysis was adopted to determine potential target genes and mechanisms of the validated tsRNAs in PAH. Results: Microarray detected 816 statistically significantly dysregulated tsRNAs, of which 243 tsRNAs were upregulated and 573 were downregulated in PAH. Eight validated tsRNAs in the results of Real-time PCR were concordant with the small RNA microarray: four upregulated (tRF3a-AspGTC-9, 5'tiRNA-31-GluCTC-16, i-tRF-31:54-Val-CAC-1 and tRF3b-TyrGTA-4) and four downregulated (5'tiRNA-33-LysTTT-4, i-tRF-8:32-Val-AAC-2, i-tRF-2:30-His-GTG-1, and i-tRF-15:31-Lys-CTT-1). The Gene Ontology analysis has shown that the verified tsRNAs are related to cellular macromolecule metabolic process, regulation of cellular process, and regulation of cellular metabolic process. It is disclosed that potential target genes of verified tsRNAs are widely involved in PAH pathways by Kyoto Encyclopedia of Genes and Genomes. Conclusion: This study investigated tsRNA profiles in idiopathic PAH and found that the dysregulated tsRNAs may become a novel type of biomarkers and possible targets for PAH.

Hospitalization Among Pulmonary Arterial Hypertension Patients With and Without Connective Tissue Disease Comorbidities Prescribed Oral Selexipag.

Patients with connective tissue disorders (CTD) and pulmonary arterial hypertension (PAH) have a poorer prognosis than those with other PAH etiologies. This study assessed the impact of CTD on healthcare outcomes among PAH patients with and without CTD comorbidities that were treated with oral selexipag. The study utilized Optum's de-identified Clinformatics® Data Mart Database (2007-2021) from January 1, 2014 to June 30, 2019, and identified patients with PAH without CTD and PAH with CTD treated with oral selexipag. Patients had ≥ 12-month baseline period with no requirement for a minimum follow-up period. Patients were followed until any of the following events: discontinuation of oral selexipag, or health plan disenrollment, or death, or presence of a diagnosis claim for CTEPH, or study end date, whichever occurred first. PAH-related hospitalizations, PAH disease progression, and healthcare utilizations and costs were assessed in the follow-up period. TheCox proportional hazards model was used to evaluate the time to hospitalization and generalized linear models were used to examine healthcare costs and utilization between the two cohorts. In the analysis, 237 PAH without CTD, and 80 PAH patients with CTD comorbidities prescribed oral selexipag were included. The PAH without CTD comorbidities cohort was older (65 vs. 63years old), had proportionately less females (72 vs. 83%), and higher comorbidity burden than PAH with CTD comorbidities (mean CCI index 3 vs. 2). After adjusting for potential confounders, the risk for PAH-related hospitalization (hazard ratio (HR) 1.13, p value 0.641), all-cause hospitalization (HR 1.09, p value: 0.765), and PAH disease progression (HR 1.14, p value 0.522) between the two cohorts were similar. After adjusting for baseline demographic and clinical characteristics, PAH with CTD comorbidities incurred higher total mean all-cause PAH-related medical care costs compared to PAH without CTD comorbidities. In this real-world study, the risk of hospitalization and PAH disease progression were similar between the two cohorts who received oral selexipag. The results from this study corroborate findings of the GRIPHON post hoc analysis of PAH-associated CTD patients and support oral selexipag use in PAH-CTD patients.

Patient Satisfaction with a Dedicated Infusion Pump for Subcutaneous Treprostinil to Treat Pulmonary Arterial Hypertension

Background and Objectives: Parenteral prostacyclins are crucial in the pharmacological treatment of pulmonary arterial hypertension (PAH). Indeed, subcutaneous administration of treprostinil has been associated with considerable clinical and hemodynamic improvement, right-sided heart reverse remodeling, and long-term survival benefit. However, evidence on patient perceptions about handling a subcutaneous infusion pump for self-treatment administration and nurse views about training the patients are lacking. This study aimed to describe the perception of PAH patients and nurses regarding the use of the new portable I-Jet infusion pump for the self-administration of subcutaneous treprostinil, as well as its real-world training needs. Materials and Methods: The study is an open, observational, prospective, single-center, non-interventional study. Patients with PAH on stable therapy with subcutaneous treprostinil were invited to take part in the study at their start of use of the portable I-Jet infusion pump for the self-administration of treatment. Participants filled in a questionnaire to report their satisfaction with the use of the pump, as well as their compliance, confidence, convenience, preferences, technical issues, and perceptions of the training they received. Results: Thirteen patients completed the questionnaire after being on the pump for 2 months: 69% were females and the mean age was 51 years. The most frequent PAH etiologies were congenital heart disease (46.2%) and idiopathic PAH (38.4%). Most patients were either World Health Organization (WHO) functional class II (53.8%) or III (46.2%). Ten patients (76.9%) found the pump easy and convenient to live with. All patients declared themselves to be fully compliant and confident in using the pump (n = 13) at the end of the study follow-up. Ten patients (76.9%) would choose the new pump in the future. None of the patients made reference to technical issues that required additional hospital visits. Eight patients (61.6%) reported that learning how to use the I-Jet infusion pump was easy or very easy, and none considered that further training was needed. One trainer nurse was interviewed and confirmed the satisfaction of patients and the simplicity of usage and training. Conclusions: PAH patients were highly satisfied with the use of the new portable I-Jet infusion pump for self-administering subcutaneous treprostinil. Convenience and ease of use were valuable and commonly reported features. Moreover, the training requirement was simple. These preliminary findings support the routine use of the I-Jet infusion pump.

Bile acid predicts congenital portosystemic venous shunt in patients with pulmonary arterial hypertension

The etiology of pulmonary arterial hypertension (PAH) is complex, especially the investigation of rare pathogeny is difficult. Congenital portosystemic venous shunt (CPSS) is a rare congenital anomaly in which the portal blood completely or partially bypasses the liver through a congenital portosystemic shunt, and drains directly into the inferior vena cava (IVC) (Howard and Davenport in J Pediatr Surg 32:494–497, 1997).CPSS is an uncommon cause of PAH (Christiane et al. in J Pediatr Gastroenterol Nutr 56:675–681, 2013), and often covered by other pathogenic factors. The clinical manifestations of CPSS-associated PAH are not specific, thus making it difficult to distinguish from PAH caused by other pathogenetic factors based on clinical presentations alone. This is a retrospective analysis of data from six patients with CPSS at a single center. Of these, five were diagnosed as PAH: four were also associated with other predisposing factors of pulmonary hypertension (PH). All patients had high serum bile concentration and high cardiac output. The aim of this retrospective study was to investigate the clinical recognition of PAH secondary to CPSS. The concentration of serum bile acid and cardiac output can be used as two important non-invasive indicators in clinical practice. Thus far, few studies have reported the clinical outcomes of CPSS-associated PAH specifically (Anna et al. in Hepatology 71:658–669, 2020;Franchi-Abella et al. in J Pediatr Gastroenterol Nutr 51:322–330, 2010;Uike et al. in Pediatr Pulmonol 53:505–511, 2018;). In the current study, such patients carried a poor prognosis if left untreated, or treated with pulmonary vasodilators alone.

Derivation of a Risk Score (REVEAL-ECHO) Based on Echocardiographic Parameters of Patients With Pulmonary Arterial Hypertension

Multiparametric risk assessment tools determine mortality risk in patients with pulmonary arterial hypertension (PAH) by combining invasive and noninvasive variables so management strategies can be tailored to individuals. Can a risk score based on common echocardiographic parameters risk-stratify patients with PAH? A Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) echocardiographic risk score (REVEAL-ECHO) was derived using retrospective echocardiographic data from 2,400 adult patients with PAH enrolled in the REVEAL registry database. A stepwise Cox regression model identified echocardiographic parameters significantly predictive of survival. Values were assigned to each selected parameter based on survival at 12months' follow-up (Kaplan-Meier estimates). The REVEAL-ECHO risk score was the sum of individual values. Patients were categorized as having low, intermediate, or high risk based on Kaplan-Meier-predicted 12-month survival. The risk score included four echocardiographic parameters-right ventricular (RV) chamber enlargement, reduced RV systolic function, tricuspid regurgitation severity, and pericardial effusion-and accounted for PAH etiology. Higher REVEAL-ECHO risk scores signaled lower probability of 12-month survival. Statistically significant separation of mortality risk was observed among the risk strata: intermediate vslow (hazard ratio [HR], 1.43; 95%CI, 1.17-1.75; P= .0004) and high vslow (HR, 2.60; 95%CI, 2.19-3.10; P< .0001). Augmentation of the REVEAL Lite 2 risk calculator with REVEAL-ECHO risk scores achieved separation of REVEAL Lite 2 into four risk groups and identified a subgroup of patients with a low REVEAL Lite 2 risk score who were at higher risk (intermediate-low risk) and a subgroup of patients with an intermediate REVEAL Lite 2 risk score who also were at higher risk (intermediate-high risk). A REVEAL-ECHO risk score, derived using four echocardiographic parameters, may discriminate risk further when used as an adjunct to current risk assessment scores. Further validation is required.

Long-term impact of add-on sequential triple combination therapy in pulmonary arterial hypertension: real world experience.

Sequential triple combination therapy is recommended for pulmonary arterial hypertension (PAH) patients who are not at therapeutic goal on dual therapy, but long-term data on efficacy and safety is scarce. To assess the long-term impact of sequential triple combination therapy in patients with PAH who are not at goal on dual combination therapy. We performed a retrospective observational study in a racially/ethnically diverse cohort of consecutive PAH patients on a stable dual therapy regimen who remained in intermediate- or high-risk category and were subsequently initiated on sequential triple combination therapy. We studied interval change in functional, echocardiographic, and hemodynamic parameters, REVEAL 2.0 risk category and ERS/ESC 2022 simplified four-strata risk category. Multivariate logistic regression analysis was performed to identify independent predictors of successful risk reduction (achievement or maintenance of REVEAL 2.0 low-risk category). Kaplan-Meier survival curves were created to assess the effect of risk reduction on survival. Out of 414 PAH patients seen in our program, 55 patients received add-on sequential triple combination regimen and had follow-up hemodynamic data. The mean age was 57 years, with 85% women. The most common etiology of PAH was idiopathic/heritable (41.8%). Most patients were WHO functional class III (76.4%), and 34.5% of patients were in high-risk category (REVEAL 2.0). On a median follow-up of 68 weeks, there was a significant improvement in WHO Functional Class (p < 0.001), six-minute walk distance (35 m) with 61.8% of patients achieving low-risk status by REVEAL 2.0, and a 28% of patients' improvement in pulmonary vascular resistance. Female gender was identified as a strong predictor of successful risk reduction, whereas Hispanic ethnicity estimated right atrial pressure on echocardiogram and pericardial effusion predicted lower probability of risk reduction. Patients who achieved or maintained low-risk status had significantly improved survival. Add-on sequential triple combination therapy significantly increased functional, echocardiographic, and hemodynamic parameters with improvement in risk category and survival.

Advances in targeted therapy for pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a rare and devastating pulmonary vascular disease that is associated with a variety of diseases of any age in childhood onset. •Therapeutic strategies for targeted drugs for PAH in children are based almost exclusively on data from adult studies and clinical experience of pediatric specialists. •Due to the complex etiology of PAH in children and the relative lack of clinical trial data, the selection of appropriate targeted drug therapy remains difficult. •We redefine the definition of pulmonary arterial hypertension in children and summarize the progress of targeted therapy of pulmonary arterial hypertension in children in the past ten years. • The dosage and adverse reactions were summarized, and the mechanism of action was drawn according to the available targeted drugs. It can provide theoretical support for the development of guidelines and treatment strategies for the diagnosis and treatment of pulmonary arterial hypertension in children.

Characteristics of Patients With Pulmonary Arterial Hypertension in a Pulmonary Hypertension Association-Accredited Comprehensive Care Center: A Contrast in Features When Compared With US National Registry Data.

Background Since the initial description in the 1980s, our understanding of the diversity of pulmonary arterial hypertension (PAH) has continued to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data from the United States Pulmonary Hypertension Scientific Registry (USPHSR). Study Design Investigators at the University of Utah Pulmonary Hypertension Program prospectively enrolled adult patients diagnosed with WHO Group 1 PAH, who were evaluated between August 2020 and November 2021 in a program-specific registry. Patient exposure and health histories were collected through structured interviews and questionnaires, along with clinical data and medication use. A total of 242 patients were enrolled in the University of Utah Pulmonary Hypertension Registry (UUPHR). Results Of the 242 enrolled patients, the most common etiology was associated PAH (APAH), accounting for 71.1% of the population. The second largest etiology was idiopathic PAH (IPAH) at 26.4%. The remaining patients were distributed between familial PAH (FPAH), pulmonary veno-occlusive disease (PVOD), and others. Of the total population classified as APAH, 39% of cases were noted as secondary to connective tissue disease (CTD) and 33% as toxin-induced. These represented 28% and 24% of the total population, respectively. Conclusions In this US-based accredited academic medical center, the etiology of PAH in our patient population contrasts with national registry data. In the UUPHR, APAH, specifically CTD-PAH and toxin-associated PAH, accounts for the majority of patients with PAH. This contrasts with IPAH, which nationally is the most reported cause of PAH. Differences in our population may reflect the regional variation of the referral site, but it is noteworthy for its contrast with historically reported phenotypes.

Biomarker-based approach to determine etiology and severity of pulmonary hypertension: Focus on microRNA.

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the pulmonary arteries, and defined by elevated pulmonary arterial pressure, measured during right heart catheterization. There are three main challenges to the diagnostic and therapeutic process of patients with PAH. First, it is difficult to differentiate particular PAH etiology. Second, invasive diagnostic is required to precisely determine the severity of PAH, and thus to qualify patients for an appropriate treatment. Third, the results of treatment of PAH are unpredictable and remain unsatisfactory. MicroRNAs (miRNAs) are small non-coding RNAs that regulate post transcriptional gene-expression. Their role as a prognostic, and diagnostic biomarkers in many different diseases have been studied in recent years. MiRNAs are promising novel biomarkers in PAH due to their activity in various molecular pathways and processes underlying PAH. Lack of biomarkers to differentiate between particular PAH etiology and evaluate the severity of PAH, as well as paucity of therapeutic targets in PAH open a new field for the possibility to use miRNAs in these applications. In our article, we discuss the potential of miRNAs use as diagnostic tools, prognostic biomarkers and therapeutic targets in PAH.

Comparison of clinical and economic burden of pulmonary arterial hypertension patients with and without connective tissue disease treated with macitentan

Abstract Introduction Patients with pulmonary arterial hypertension (PAH) and connective tissue disease (CTD) have a poorer prognosis than those diagnosed with other PAH etiologies. Purpose To compare the clinical and economic burden among PAH patients with and without CTD (PAH-CTD/PAH non-CTD) treated with macitentan. Methods This retrospective study used the Optum Clinformatics DataMart to identify PAH-CTD and PAH non-CTD patients aged ≥18 years and prescribed macitentan from 01JAN2015–30JUN2019. The index date was the date of the first macitentan claim. Patients had to have ≥12 months of continuous enrollment before index and were followed until earliest of macitentan discontinuation, health plan disenrollment, death, or study end. Patients in the PAH-CTD cohort had to have a claim for a CTD condition at any time during the 12-month baseline period. Patients with a baseline claim for any PAH medication, chronic thromboembolic pulmonary hypertension, prior atrial septostomy or lung transplant were excluded. Descriptive analysis comprised means, standard deviations, medians, and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Multivariable analyses (Cox proportional hazards and generalized linear models) adjusting for baseline characteristics were used to compare time to PAH-related and all-cause hospitalization, disease progression (death, lung transplant, atrial septostomy or addition of intravenous/subcutaneous prostanoids), and PAH- and all-cause related medical (inpatient and outpatient) costs between the two cohorts with PAH non-CTD as reference. Results The analysis included 203 PAH-CTD and 750 PAH non-CTD patients treated with macitentan. Versus PAH non-CTD, PAH-CTD patients were younger, had proportionately more females, and lower Charlson Comorbidity Index (CCI) scores (Table). The proportion of patients with a baseline hospitalization, length of stay and inpatient costs were similar across groups. There were no significant differences observed in time to PAH-related hospitalization (hazard ratio [HR]=0.99; p=0.910), all-cause hospitalization (HR=1.13; p=0.195), or disease progression (HR=1.00; p-value=0.973) for the PAH-CTD cohort (PAH non-CTD as reference). All-cause medical costs were similar between the cohorts ($3,836 per patient per month [PPPM] for PAH CTD vs $3,521 PPPM for PAH non-CTD, p=0.362). PAH-CTD patients incurred higher mean PAH-related medical costs vs PAH non-CTD ($2,806 PPPM vs $1,961 PPPM, p=0.047). Conclusion The study suggests that risk of all-cause and PAH-related hospitalization and disease progression did not differ for PAH-CTD and PAH non-CTD patients. Treatment with macitentan in the real world appears to confer similar clinical benefits in both PAH-CTD and PAH non-CTD groups. All-cause costs did not differ between the two cohorts but PAH-related costs were significantly higher in PAH-CTD patients suggesting an incremental burden associated with CTD. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Janssen Scientific Affairs, LLC

Concomitant initiation of combination therapy with macitentan and tadalafil in pulmonary arterial hypertension (PAH) patients with comorbidities: real-world data from OPUS and OrPHeUS

Abstract Background Guidelines for the management of pulmonary arterial hypertension (PAH) recommend early combination therapy of an endothelial receptor antagonist (ERA) and a phosphodiesterase type-5 inhibitor (PDE5i) [1]. There is, however, limited guidance about the management of PAH patients with comorbidities. Purpose To describe the demographics, clinical characteristics, safety, tolerability, and outcomes associated with initiation of the ERA macitentan and the PDE5i tadalafil in patients with comorbidities in the US OPsumit® USers (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) combined dataset. Methods This analysis reports data from the OPUS registry (Apr 2014–Jun 2020) and OrPHeUS medical chart review (Oct 2013–Mar 2017) on PAH patients initiating macitentan and tadalafil (M+T) combination therapy, in any order, as concomitant initiation (≤60 days apart, concomitant initiation group). The index date was defined as the start date of the second therapy (i.e., the start of combination therapy). Patients were further grouped by the number of comorbidities present prior to or at macitentan initiation: systemic hypertension, diabetes, renal insufficiency, BMI ≥30 kg/m2, other signs of right heart failure and atrial fibrillation. Results are presented descriptively alongside results for all PAH patients receiving M+T combination therapy (overall M+T group). Results Of the 1336 PAH patients that received M+T combination therapy, 431 (32%) were in the concomitant initiation group. In the concomitant initiation and overall M+T groups, respectively: 72% and 68% had ≥1 comorbidity, and the most common were systemic hypertension (47% and 47%), obesity (32% and 26%) and diabetes (23% and 22%). Patients were more likely to be older, male and have idiopathic/heritable PAH with increasing comorbidity burden (Table 1). Patients in the concomitant initiation group were more likely to be incident (median time from diagnosis: 1–2 months vs 9–24 months in the overall M+T group; Table 1). Most patients had ≥1 adverse event (AE); in both groups, patients with a high comorbidity burden (≥3) were more likely to have had an AE and to have discontinued treatment (Table 2). The incidence rate of first all-cause hospitalisation and mortality by comorbidity was comparable between the concomitant initiation and overall M+T groups. Conclusions In the real-world, concomitant initiation of M+T is used in PAH patients with comorbidities, usually shortly after diagnosis. Patient characteristics were similar for the concomitant initiation and overall M+T groups, with the exception of time from diagnosis. At index date, age, gender proportion, and PAH aetiology differed between the comorbidity groups. The safety profile of M+T combination therapy in the concomitant initiation group was consistent with that in the overall M+T group. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson &amp; Johnson

Schistosomiasis-Associated Pulmonary Arterial Hypertension

Schistosomiasis is a major cause of group 1 pulmonary arterial hypertension (PAH) worldwide. Schistosomiasis results from a parasitic infection present in over 200 million individuals worldwide. Schistosomiasis-associated PAH was initially thought to be obstructive due to egg embolization but has a pulmonary vascular pathology like other forms of group 1 PAH and can be treated using conventional PAH therapies. Mechanisms that underlie the development of schistosomiasis-associated PAH include type 2 inflammation which triggers TGF-β signaling; importantly, TGF-β signaling is a pathway shared with other PAH etiologies. However, many things which are unknown about this disease remain, including if the lung vascular pathology results from egg embolization causing localized inflammation and vessel remodeling, or if this is a form of portopulmonary hypertension resulting from schistosomiasis liver disease.

Baseline Sex Differences in Pulmonary Arterial Hypertension Randomized Clinical Trials.

Rationale: Sex-based differences in pulmonary arterial hypertension (PAH) are known, but the contribution to disease measures is understudied. Objectives: We examined whether sex was associated with baseline 6-minute-walk distance (6MWD), hemodynamics, and functional class. Methods: We conducted a secondary analysis of participant-level data from randomized clinical trials of investigational PAH therapies conducted between 1998 and 2014 and provided by the U.S. Food and Drug Administration. Outcomes were modeled as a function of an interaction between sex and age or sex and body mass index (BMI), respectively, with generalized mixed modeling. Results: We included a total of 6,633 participants from 18 randomized clinical trials. A total of 5,197 (78%) were female, with a mean age of 49.1 years and a mean BMI of 27.0 kg/m2. Among 1,436 males, the mean age was 49.7 years, and the mean BMI was 26.4 kg/m2. The most common etiology of PAH was idiopathic. Females had shorter 6MWD. For every 1 kg/m2 increase in BMI for females, 6MWD decreased 2.3 (1.6-3.0) meters (P < 0.001), whereas 6MWD did not significantly change with BMI in males (0.31 m [-0.30 to 0.92]; P = 0.32). Females had lower right atrial pressure (RAP) and mean pulmonary artery pressure, and higher cardiac index than males (all P < 0.03). Age significantly modified the sex by RAP and mean pulmonary artery pressure relationships. For every 10-year increase in age, RAP was lower in males (0.5 mm Hg [0.3-0.7]; P < 0.001), but not in females (0.13 [-0.03 to 0.28]; P = 0.10). There was a significant decrease in pulmonary vascular resistance (PVR) with increasing age regardless of sex (P < 0.001). For every 1 kg/m2 increase in BMI, there was a 3% decrease in PVR for males (P < 0.001), compared with a 2% decrease in PVR in females (P < 0.001). Conclusions: Sexual dimorphism in subjects enrolled in clinical trials extends to 6MWD and hemodynamics; these relationships are modified by age and BMI. Sex, age, and body size should be considered in the evaluation and interpretation of surrogate outcomes in PAH.

Advances in genome-wide association study of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a complex disease caused by multiple factors, including idiopathic PAH, heritable PAH, disease related PAH etc. Due to the high genetic heterogeneity, clinical characteristics and prognosis of PAH patients vary greatly. At present, the specific pathogenesis of PAH is unclear, and the diagnosis and treatment of PAH remain to be explored. Therefore, the study of genetic susceptibility to PAH is of great significance for understanding the occurrence and development of the disease. With the development of genome-wide association study (GWAS), a large number of genetic variations related to etiology, clinical manifestations, prognosis and treatment of PAH have been identified. This review summarizes the recent progress in the application of GWAS in the study of genetic susceptibility of PAH, and provides new insights for further exploration of the development and individualized management of PAH.

Symptom phenotypes in pulmonary arterial hypertension: The PAH "symptome".

Women with pulmonary arterial hypertension (PAH) experience multiple symptoms, including dyspnea, fatigue, and sleep disturbance, that impair their health‐related quality of life (HRQOL). However, we know little about phenotypic subgroups of patients with PAH with similar, concurrent, multiple symptoms. The objectives of this study were to define the “symptome” by symptom cluster phenotypes and compare characteristics such as biomarkers, cardiac structure and function (echocardiography), functional capacity (6‐min walk distance), and HRQOL between the groups. This cross‐sectional study included 60 women with PAH. Subjects completed an assessment battery: Pulmonary Arterial Hypertension Symptom Scale, Pittsburgh Sleep Quality Index, Multidimensional Dyspnea Profile, Patient‐Reported Outcomes Measurement Information System (PROMIS®) Physical Function, PROMIS® Sleep‐Related Impairment, and the emPHasis‐10. Subjects also underwent transthoracic echocardiography, phlebotomy, 6‐min walk distance, and actigraphy. The three symptoms of dyspnea, fatigue, and sleep disturbance were used to define the symptom clusters. Other PAH symptoms, plasma and serum biomarkers, cardiac structure and function (echocardiography), exercise capacity (6‐min walk distance), sleep (actigraphy), and HRQOL were compared across phenotypes. The mean age was 50 ± 18 years, 51% were non‐Hispanic white, 32% were non‐Hispanic Black and 40% had idiopathic PAH. Cluster analysis identified Mild (n = 28, 47%), Moderate (n = 20, 33%), and Severe Symptom Cluster Phenotypes (n = 12, 20%). There were no differences for age, race, or PAH etiology between the phenotypes. WHO functional class (p < 0.001), norepinephrine levels (p = 0.029), right atrial pressure (p = 0.001), physical function (p < 0.001), sleep onset latency (p = 0.040), and HRQOL (p < 0.001) all differed significantly across phenotypes. We identified three distinctive symptom cluster phenotypes (Mild, Moderate, and Severe) for women with PAH that also differed by PAH‐related symptoms, physical function, right atrial pressure, norepinephrine levels, and HRQOL. These phenotypes could suggest targeted interventions to improve symptoms and HRQOL in those most severely affected.

Hispanic Ethnicity and Social Determinants of Health in Pulmonary Arterial Hypertension: The Pulmonary Hypertension Association Registry.

Rationale: There is a noticeable underrepresentation of minorities in clinical trials and registries in pulmonary arterial hypertension (PAH). Prior studies evaluating the association between Hispanic ethnicity and clinical outcomes in patients with PAH have not assessed the socioeconomic profile of Hispanic individuals or the significance of social determinants of health in clinical outcomes. Objectives: To determine the association between Hispanic ethnicity, social determinants of health, and clinical outcomes in PAH. Methods: This was a prospective cohort study of adult participants with PAH enrolled in the Pulmonary Hypertension Association Registry, a multicenter U.S.-based registry of patients treated at pulmonary hypertension care centers. Participants were classified as Hispanics and non-Hispanic White individuals, based on self-reported ethnicity. A comparison of baseline clinical and sociodemographic characteristics between groups was performed as well using absolute standardized differences (ASD). The primary outcome of the study was to assess transplant-free survival between Hispanics and non-Hispanic White individuals. A Cox proportional hazards model was used for the multivariable analysis after adjusting for age, sex, PAH etiology, annual income, education level, and health insurance. Results: A total of 683 individuals were included, 98 (14.3%) of Hispanic ethnicity. Hispanic patients had impaired access to health care (31.6% vs. 12.9% Medicaid/uninsured; ASD, 0.35), lower education level (72.6% vs. 94.0% high school graduates or higher; ASD, 0.60), and lower annual income (32.0% vs. 17.4% with income <20,000 U.S. dollars; ASD, 0.47), compared with non-Hispanic White individuals. Hispanic patients had a higher frequency of emergency room visits and a higher number of hospitalizations, despite having similar disease severity (incidence rate ratio, 1.452; 95% confidence interval [CI], 1.326-1.590; and 1.428; 95% CI, 1.292-1.577, respectively). Although the unadjusted analysis showed a lower transplant/death hazard ratio for Hispanics (hazard ratio, 0.47; 95% CI, 0.24-0.94; P = 0.032), there was no association between Hispanic ethnicity and outcome in the multivariable model after adjusting for social determinants of health and other covariates (HR, 0.76; 95% CI, 0.35-1.62; P = 0.474). Conclusions: Hispanic ethnicity was not associated with differences in survival after adjusting for social determinants of health and other factors. Social determinants of health are important to consider when assessing the association between ethnicity and outcomes in PAH.

The Clinical Experience of Macitentan in pulmonary hypertension in Indian cohort: 12-months follow-up

Abstract Funding Acknowledgements Type of funding sources: None. AIM AND OBJECTIVE Macitentan, an endothelin receptor antagonist, has been shown to be effective and safe in the treatment of pulmonary arterial hypertension (PAH) in multiple randomized clinical trials, including SERAPHIN, focusing on morbidity and mortality reduction. The goal of this study was to show the clinical and echocardiographic improvement with macitentan in Indian patients with PAH. METHODS We conducted a retrospective study of 20 patients with various etiologies of PAH who received macitentan treatment in a single institution between June 2018 and June 2019. Of the total cases, 55% of the patients took conventional PAH therapies. We assessed the World Health Organization functional class (WHO-FC), 6-minute walking distance (6MWD), N-terminal prohormone brain natriuretic peptide level (NT-pro-BNP), and echocardiographic data such as tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure (sPAP), and the presence of pericardial effusion at baseline and 12-month follow-up. RESULTS The study involved 20 PAH patients, 70 % of whom were female. The majority (50%) were in WHO FC II, while 35% were in FC III, and 15% were in FC IV. At the start of the macitentan therapy, the average age was 43.4 years. After 12-months of macitentan medication, 85% of patients showed significant improvement in their FC, 6-minute walking distance test (p &amp;lt; 0.0001; Fig.-1), and plasma levels of NT-pro BNP were significantly reduced (p &amp;lt; 0.0001). Echocardiographic parameters such as TAPSE and sPAP have also improved (p &amp;lt; 0.0001). CONCLUSION Our findings indicate that macitentan has been well-tolerated and beneficial in Indian patients with PAH, and further future research is required to verify these results. Abstract Figure.

NOTCH3 Mutations and CADASIL Phenotype in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Background: The etiology of pulmonary arterial hypertension associated with congenital heart disease (PAHCHD) is complicated and the phenotype is heterogeneous. Genetic defects of NOTCH3 were associated with cerebral disease and pulmonary hypertension. However, the relationship between NOTCH3 mutations and the clinical phenotype has not been reported in CHD-PAH. Methods: We eventually enrolled 142 PAH-CHD patients from Fuwai Hospital. Whole exome sequencing (WES) was performed to screen the rare deleterious variants of NOTCH3 gene. Results: This PAH-CHD cohort included 43 (30.3%) men and 99 (69.7%) women with the mean age 29.8 ± 10.9 years old. The pathogenic or likely pathogenic mutations of NOTCH3 were identified in five cases. Patients 2, 5, 8 and 11 carried the same NOTCH3 mutation c.1630C > T (pArg544Cys), which is the hot-spot mutation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Patient 3 carried the NOTCH3 mutation p.Arg75Gln that has also been reported to be associated with the CADASIL. Patients 2, 5, 8, 11 took the examination of the cerebral magnetic resonance imaging (MRI) and confirmed the phenotype of CADASIL. Conclusions: We first reported the NOTCH3 rare mutations and CADASIL phenotypes in CHD-PAH patients. The NOTCH3 rare variants were with a relatively high positive rate and CADASIL phenotypes were likely enriched in PAH-CHD patients. The preoperative neurological examination might be recommended for PAH-CHD patients to determine the surgical contraindications and reduce intraoperative neurological complications.