Managing Pulmonary Arterial Hypertension With Cardiopulmonary Comorbidities.

Pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with left-sided heart and lung diseases are most commonly easily discriminated and treated accordingly. With the changing epidemiology of PAH, however, a growing proportion of patients at the time of diagnosis present with comorbidities of varying severity. In addition to classical PAH, two distinct phenotypes have emerged: a heart failure with preserved ejection fraction-like phenotype and a lung phenotype. Importantly, the evidence supporting the currently proposed treatment algorithm for PAH has been generated mainly from PAH trials in which patients with cardiopulmonary comorbidities have been underrepresented or excluded. As a consequence, the best therapeutic approach for patients with common PAH with cardiopulmonary comorbidities remains largely unknown and requires further investigation. The present article reviews the relevant literature on the topic and describes the authors' views on the current therapeutic approach for these patients.

Investigating the "sex paradox" in pulmonary arterial hypertension: Results from the Pulmonary Hypertension Association Registry (PHAR).

BACKGROUND: Female sex is a significant risk factor for pulmonary arterial hypertension (PAH), yet males with PAH have worse survival - a phenomenon referred to as the "sex paradox" in PAH. METHODS: All adult PAH patients in the Pulmonary Hypertension Association Registry (PHAR) with congruent sex and gender were included. Baseline differences in demographics, hemodynamics, functional parameters, and quality of life were assessed by sex. Kaplan-Meier survival analysis was used to evaluate survival by sex. Mediation analysis was conducted with Cox proportional hazards regression by comparing the unadjusted hazard ratios for sex before and after adjustment for covariates. The plausibility of collider-stratification bias was assessed by modeling how large an unmeasured factor would have to be to generate the observed sex-based mortality differences. Subgroup analysis was performed on idiopathic and incident patients. RESULTS: Among the 1,891 patients included, 75% were female. Compared to men, women had less favorable hemodynamics, lower 6-minute walk distance, more PAH therapies, and worse functional class; however, sex-based differences were less pronounced when accounting for body surface area or expected variability by gender. On multivariate analysis, women had a 48% lower risk of death compared to men (Hazard Ratio 0.52, 95% Confidence interval 0.36 - 0.74, p < 0.001). Modeling found that under reasonable assumptions collider-stratification could account for sex-based differences in mortality. CONCLUSIONS: In this large registry of PAH patients new to a care center, men had worse survival than women despite having more favorable baseline characteristics. Collider-stratification bias could account for the observed greater mortality among men.

Causal effects between gut microbiota and pulmonary arterial hypertension: A bidirectional Mendelian randomization study.

BACKGROUND: Multiple studies have highlighted a potential link between gut microbes and the onset of Pulmonary Arterial Hypertension (PAH). Nonetheless, the precise cause-and-effect relationship remains uncertain. OBJECTIVES: In this investigation, we utilized a two-sample Mendelian randomization (TSMR) approach to probe the presence of a causal connection between gut microbiota and PAH. METHODS: Genome-wide association (GWAS) data for gut microbiota and PAH were sourced from MiBioGen and FinnGen research, respectively. Inverse variance weighting (IVW) was used as the primary method to explore the causal effect between gut flora and PAH, supplemented by MR-Egger, weighted median (WM). Sensitivity analyses examined the robustness of the MR results. Reverse MR analysis was used to rule out the effect of reverse causality on the results. RESULTS: The results indicate that Genus Ruminococcaceae UCG004 (OR = 0.407, P = 0.031) and Family Alcaligenaceae (OR = 0.244, P = 0.014) were protective factors for PAH. Meanwhile Genus Lactobacillus (OR = 2.446, P = 0.013), Class Melainabacteria (OR = 2.061, P = 0.034), Phylum Actinobacteria (OR = 3.406, P = 0.010), Genus Victivallis (OR = 1.980, P = 0.010), Genus Dorea (OR = 3.834, P = 0.024) and Genus Slackia (OR = 2.622, P = 0.039) were associated with an increased Prevalence of PAH. Heterogeneity and pleiotropy were not detected by sensitivity analyses, while there was no reverse causality for these nine specific gut microorganisms. CONCLUSIONS: This study explores the causal effects of eight gut microbial taxa on PAH and provides new ideas for early prevention of PAH.

Impact of the COVID-19 Pandemic on Health Care Access and Diagnosis of Pulmonary Arterial Hypertension Among Patients With Systemic Sclerosis.

OBJECTIVE: Regular clinical assessment for complications of systemic sclerosis (SSc) such as pulmonary arterial hypertension (PAH) is essential for early institution of therapy and improved outcomes. The objective of this study was to determine the impact of COVID-19 pandemic-related restrictions on health care access of patients with SSc, including screening for PAH. METHODS: South Australian and Victorian patients enrolled in the Australian Scleroderma Cohort Study were surveyed about their perceptions of the impact of the pandemic on mental well-being, access to medications, investigations, and management of SSc. Frequency of annual rheumatology assessments, pulmonary function tests (PFT), and transthoracic echocardiography (TTE) to screen for PAH were compared with rates from before the pandemic. RESULTS: A total of 312 of 810 patients with SSc responded (38.5% response); 273 were female (87.5%), the median age was 64.7 years, 77.2% had limited disease, the median illness duration was 15.6 years, 15.7% were immunosuppressed, 32.1% had interstitial lung disease, and 6.4% had PAH. A total of 65.7% of consultations were by telehealth, of which 81.2% were by telephone. Compared with respondents in South Australia (n = 109), Victorian respondents (n = 203) experiencing prolonged lockdown, reported reduced access to their rheumatologist (49.3% vs 27.9%; P = 0.004), greater use of consultation by video (17.3% vs 2.1%; P = 0.008), greater health care disruption (49.0% vs 23.2%; P < 0.001), and worse mental health (P = 0.002). Respondents reported reduced access to PFT and TTE (31.7% and 22.5%, respectively). Annual visits, PFT, TTE, and new diagnoses of PAH were reduced in 2020 to 2022 compared with 2011 to 2019. CONCLUSION: The COVID-19 pandemic-related disruption to health care for patients with SSc was associated with worse mental health and reduced screening and diagnosis of PAH, which may impact long-term outcomes.

Long-term outcome of children with newly diagnosed pulmonary arterial hypertension: results from the global TOPP registry.

BACKGROUND AND AIMS: The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global network established to gain insights into the disease course and long-term outcomes of paediatric pulmonary arterial hypertension (PAH). Previously published cohorts in paediatric PAH are obscured by survival bias due to the inclusion of both prevalent (previously diagnosed) and incident (newly diagnosed) patients. The current study aims to describe long-term outcome and its predictors in paediatric PAH, exclusively of newly diagnosed patients. METHODS AND RESULTS: Five hundred thirty-one children with confirmed pulmonary hypertension, aged ≥3 months and <18 years, were enrolled in the real-world TOPP registry at 33 centres in 20 countries, from 2008 to 2015. Of these, 242 children with newly diagnosed PAH with at least one follow-up visit were included in the current outcome analyses. During long-term follow-up, 42 (17.4%) children died, 9 (3.7%) underwent lung transplantation, 3 (1.2%) atrial septostomy, and 9 (3.7%) Potts shunt palliation (event rates: 6.2, 1.3, 0.4, and 1.4 events per 100 person-years, respectively). One-, three-, and five-year survival free from adverse outcome was 83.9%, 75.2%, and 71.8%, respectively.Overall, children with open (unrepaired or residual) cardiac shunts had the best survival rates. Younger age, worse World Health Organization functional class, and higher pulmonary vascular resistance index were identified as independent predictors of long-term adverse outcome. Younger age, higher mean right atrial pressure, and lower systemic venous oxygen saturation were specifically identified as independent predictors of early adverse outcome (within 12 months after enrolment). CONCLUSION: This comprehensive analysis of survival from time of diagnosis in a large exclusive cohort of children newly diagnosed with PAH describes current-era outcome and its predictors.

Pulmonary arterial hypertension associated with connective tissue diseases (CTD-PAH): Recent and advanced data.

Pulmonary arterial hypertension (PAH), corresponding to group 1 of pulmonary hypertension classification, is a rare disease with a major prognostic impact on morbidity and mortality. PAH can be either primary in idiopathic and heritable forms or secondary to other conditions including connective tissue diseases (CTD-PAH). Within CTD-PAH, the leading cause of PAH is systemic sclerosis (SSc) in Western countries, whereas systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are predominantly associated with PAH in Asia. Although many advances have been made during the last two decades regarding classification, definition early screening and risk stratification and therapeutic aspects with initial combination treatment, the specificities of CTD-PAH are not yet clear. In this manuscript, we review recent literature data regarding the updated definition and classification of PAH, pathogenesis, epidemiology, detection, prognosis and treatment of CTD-PAH.

Methamphetamine-associated pulmonary arterial hypertension: data from the national biological sample and data repository for pulmonary arterial hypertension (PAH Biobank).

OBJECTIVE: This study compares the clinical and haemodynamic severity of methamphetamine-associated pulmonary arterial hypertension (MA-PAH) with idiopathic pulmonary arterial hypertension (IPAH) and connective tissue-associated pulmonary arterial hypertension (CTD-PAH). It also examines sex differences in clinical and physiological parameters among those with MA-PAH. DESIGN: This is a cross-sectional study using clinically derived data from the National Biological Sample and Data Repository for Pulmonary Arterial Hypertension (PAH biobank), a US-based registry, to compare clinical and physiological characteristics between males and females with MA-PAH. POPULATION: The analysis included 1830 patients enrolled in the PAH biobank, with a diagnosis of MA-PAH (n=42), IPAH (n=1073), or CTD-PAH (n=715). MAIN OUTCOME MEASURES: The study assessed and compared the clinical and haemodynamic parameters of patients with MA-PAH, IPAH and CTD-PAH. RESULTS: Among the patients analysed, 42 had MA-PAH, with 69.1% being female. There were no statistically significant differences in functional class among patients with MA-PAH, IPAH and CTD-PAH. The per cent predicted 6-min walk distance (6MWD) was comparable between the three groups. Patients with MA-PAH had similar mean pulmonary artery pressure and pulmonary vascular resistance to patients with IPAH but higher compared with patients with CTD-PAH. Male patients with MA-PAH exhibited a worse functional class and lower per cent predicted 6MWD, but no significant differences in haemodynamic findings were observed between the sexes. CONCLUSION: There were no differences in haemodynamic between MA-PAH and IPAH but we found that MA-PAH differed from CTD-PAH. The study did not find evidence of sex differences in MA-PAH. Further research is necessary to identify risk factors and underlying mechanisms of MA-PAH, particularly considering the increasing prevalence of methamphetamine use. Such investigations will contribute to the development of effective prevention and treatment strategies for this condition.

Pharmacological management of connective tissue disease-associated pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe, progressive pulmonary vasculopathy (Group 1 Pulmonary Hypertension (PH)) that complicates the course of many connective tissue diseases (CTD). Detailed testing is required to differentiate PAH from other types of PH caused by CTD such as left heart disease (Group 2 PH), pulmonary parenchymal disease (Group 3 PH), and chronic thromboembolic pulmonary hypertension (Group 4 PH). PAH is most frequently seen in systemic sclerosis but can also be seen with systemic lupus erythematosus, mixed CTD, and primary Sjogren's syndrome. AREAS COVERED: This review discusses the epidemiology of CTD-associated PAH, outlines the complex diagnosis approach, and finishes with an in-depth discussion on the current treatment paradigm. Focus is placed on challenges faced in the treatment of CTD-associated PAH, (decreased efficacy and poorer tolerance of pharmacological therapies) and includes a discussion on the future investigational treatments. EXPERT OPINION: Despite significant advances over the past decades with more aggressive treatment algorithms, CTD-associated PAH patients continue to have poorer survival compared to those with idiopathic PAH. This review highlights factors leading to disparate outcomes compared to other forms of PAH, and discusses on further improvements that may increase quality of life and survival for CTD-associated PAH patients.

A prognostic model for systemic lupus erythematosus-associated pulmonary arterial hypertension: CSTAR-PAH cohort study.

BACKGROUND: Pulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus, but there are no tools specialized for predicting survival in systemic lupus erythematosus-associated pulmonary arterial hypertension. RESEARCH QUESTION: To develop a practical model for predicting long-term prognosis in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. METHODS: A prognostic model was developed from a multicenter, longitudinal national cohort of consecutively evaluated patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. The study was conducted between November 2006 and February 2020. All-cause death was defined as the endpoint. Cox regression and least absolute shrinkage and selection operators were used to fit the model. Internal validation of the model was assessed by discrimination and calibration using bootstrapping. RESULTS: Of 310 patients included in the study, 81 (26.1%) died within a median follow-up of 5.94 years (interquartile range 4.67-7.46). The final prognostic model included eight variables: modified World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, estimated glomerular filtration rate, thrombocytopenia, mild interstitial lung disease, N-terminal pro-brain natriuretic peptide/brain natriuretic peptide level, and direct bilirubin level. A 5-year death probability predictive algorithm was established and validated using the C-index (0.77) and a satisfactory calibration curve. Risk stratification was performed based on the predicted probability to improve clinical decision-making. CONCLUSIONS: This new risk stratification model for systemic lupus erythematosus-associated pulmonary arterial hypertension may provide individualized prognostic probability using readily obtained clinical risk factors. External validation is required to demonstrate the accuracy of this model's predictions in diverse patient populations.

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients. OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH. METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response. RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response. CONCLUSION: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Risk factors of pulmonary arterial hypertension in patients with systemic lupus erythematosus: A meta-analysis.

OBJECTIVE: To determine the risk factors of pulmonary arterial hypertension (PAH) related to systemic lupus erythematosus (SLE) through systematic reviews and meta-analyses. METHODS: We undertook electronic search strategies using Medline via PubMed, Embase, Web of Science, and Cochrane Library up to April 11, 2023. Study selection and data extraction were performed by 2 authors independently. We made risk of bias judgments based on the Newcastle-Ottawa Scale (NOS). Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to estimate the overall effect sizes of potential risk factors for PAH in SLE patients. Univariate and multivariate meta-regression models were used to assess the independent effects of each risk factor on PAH. Sensitivity analyses were also conducted to explore potential sources of heterogeneity. RESULTS: A total of 19 articles were included in this meta-analysis, and the results showed that gender (female) [RR = 1.04, 95% CI (1.02, 1.06), p = .0001], interstitial lung disease [RR = 4.36, 95% CI (2.42, 7.85), p = .0001], alopecia [RR = 1.39, 95% CI (1.06, 1.83), p = .017], Raynaud's phenomenon [RR = 1.83, 95% CI (1.41, 2.37), p = .0001], systemic hypertension [RR = 1.30, 95% CI (1.07, 1.58), p = .007], serositis [RR = 2.29, 95% CI (1.89, 2.77), p = .0001], pericardial effusion [RR = 3.33, 95% CI (2.20, 5.05), p = .0001], anti-RNP [RR = 1.86, 95% CI (1.19, 2.91), p = .006], anti-SSA [RR = 1.28, 95% CI (1.01, 1.62), p = .041], anti-SSB [RR = 1.38, 95% CI (1.19, 1.60), p = .0001], anti-U1RNP [RR = 1.58, 95% CI (1.07, 2.34), p = .023], thrombocytopenia [RR = 1.38, 95% CI (1.14, 1.68), p = .001], and current smokers [RR = 2.20, 95% CI (1.19, 4.06), p = .012] were all risk factors for PAH related to SLE. CONCLUSION: PAH is a serious complication of SLE. Since prognosis of SLE patients after the occurrence of PAH is poor, routine examination should be conducted for SLE patients with PAH risk factors.

Prevalence and Determinants of Delay in Time-to-Diagnosis for Pulmonary Arterial Hypertension Patients in Gansu China: A Observational Cohort Study.

Current studies of patients with pulmonary arterial hypertension (PAH) have shown a significant diagnostic delay. However, the causes and risk factors for this delay are not been well explored in Chinese population. This study aimed to assess the status of diagnostic delay in patients with PAH in China. Additionally, we identified factors associated with the delay. Demographic and clinical data were collected from 153 PAH patients admitted to three tertiary hospitals in Gansu, China, from March 2020 to October 2022. Based on the recorded date, the diagnostic delay was divided into patient delay and health system delay. For analysis, we divided diagnostic delay into 2 groups (≤3 years and >3 years). Factors associated with delay were identified by binary logistic regression. The median diagnostic delay was 3 years (IQR: 0.25-5.88). Binary logistic regression analysis showed that male (OR = 2.48, 95% CI: 1.10-5.58), those with junior high school or below (OR = 3.65, 95% CI: 1.36-9.78), living far away from the tertiary hospital (OR = 2.66, 95% CI: 1.14-6.18), initially visit hospital before 2018 (OR = 3.82, 95% CI: 1.68-8.71), and visit hospital at county level or below (OR = 3.80, 95% CI: 1.42-10.18) were risk factor for diagnostic delay (>3 years). Despite increased awareness, most patients with PAH in Gansu, China still experienced a delay in diagnosis of more than 3 years. Male sex, lower educational background, and being away from tertiary hospitals are risk factors for delay. Furthermore, factors impacting time-to-diagnosis and its impact should be continuously evaluated as therapeutic strategies continue to evolve and improve.

The prevalence of pulmonary arterial hypertension in patients with mixed connective tissue disease: a systematic review and meta-analysis.

OBJECTIVES: The prevalence and outcome of mixed connective tissue disease-associated pulmonary arterial hypertension (MCTD-PAH) has not been well understood. Our aim was to review the current knowledge on the prevalence, severity, and mortality of MCTD-PAH. We also aimed to examine the prevalence trend of MCTD-PAH over the years. METHODS: PubMed/Medline, Embase, Scopus and Web of Science electronic databases were searched for the published randomised controlled clinical trials (RCTs) and observational/original studies on PAH in patients with MCTD from January 1972 to December 2020. RESULTS: The results were pooled using random-effects meta-analysis based on DerSimonian and Laird method. A total of 983 patients from eight studies were included in the meta-analysis (K=8, n=983). Pooled prevalence of PAH in MCTD patients was 12.53% [95% CI 8.30-18.48%] with significant level statistical heterogeneity (tau2=0.30, tau=0.55, i2 83.3%, H=2.13 Q(df,7)=31.90, p=0.001). There was no association between PAH and female gender or age. The percentage of deaths in MCTD patients due to PAH varied and reached up to 81.8%. CONCLUSIONS: This is the first systematic review and meta-analysis investigating the prevalence of PAH in patients with MCTD and it revealed an overall prevalence of PAH in patients with MCTD of 12.53%. Our results showed trends of reduced prevalence of MCTD-PAH over last four decade, reconfirmed the lower prevalence rate in recent studies, but revealed an increased mortality rate. We also determined the low impact of the age, gender, and interstitial lung disease on MCTD-PAH.

Performance of risk stratification scores and role of comorbidities in older vs younger patients with pulmonary arterial hypertension.

BACKGROUND: Risk scores are important tools for the prognostic stratification of pulmonary arterial hypertension (PAH). Their performance and the additional impact of comorbidities across age groups is unknown. METHODS: Patients with PAH enrolled from 2001 to 2021 were divided in ≥65 years old vs <65 years old patients. Study outcome was 5-year all-cause mortality. French Pulmonary Hypertension Network (FPHN), FPHN noninvasive, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL 2.0) risk scores were calculated and patients categorized at low, intermediate and high risk. Number of comorbidities was calculated. RESULTS: Among 383 patients, 152 (40%) were ≥65 years old. They had more comorbidities (number of comorbidities 2, IQR 1-3, vs 1, IQR 0-2 in <65 years patients). Five-year survival was 63% in ≥65 vs 90% in <65 years. Risk scores correctly discriminated the different classes of risk in the overall cohort and in the older and younger groups. REVEAL 2.0 showed the best accuracy in the total cohort (C-index 0.74, standard error-SE- 0.03) and older (C-index 0.69, SE 0.03) patients, whereas COMPERA 2.0 performed better in younger patients (C-index 0.75, SE 0.08). Number of comorbidities was associated with higher 5-year mortality, and consistently increased the accuracy of risk scores, in younger but not in older patients. CONCLUSIONS: Risk scores have similar accuracy in the prognostic stratification of older vs younger PAH patients. REVEAL 2.0 had the best performance in older patients and COMPERA 2.0 had it in younger patients. Comorbidities increased the accuracy of risk scores only in younger patients.

Effects of COVID-19 pandemic on the management of pulmonary hypertension.

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters.

Characteristics, Long-term Survival, and Risk Assessment of Pediatric Pulmonary Arterial Hypertension in China: Insights From a National Multicenter Prospective Registry.

BACKGROUND: Registry-based studies of pediatric pulmonary arterial hypertension (PPAH) are scarce in developing countries, including China. The PPAH risk assessment tool needs further evaluation and improvement. RESEARCH QUESTION: What are the characteristics and long-term survival of PPAH in China and what is the performance of the PPAH risk model in Chinese patients? STUDY DESIGN AND METHODS: Patients with PAH were enrolled in the national prospective multicenter registry from August 2009 through December 2019. Children 3 months to 18 years of age at the time of PAH diagnosis were analyzed. RESULTS: A total of 247 children with PAH were enrolled. The median patient age was 14.8 years, and 58.3% of patients were female. Most patients had a diagnosis of PAH associated with congenital heart disease (CHD; 61.5%) and idiopathic or heritable PAH (37.7%). The median time from symptom onset to PAH diagnosis was 24 months. The mean pulmonary artery pressure and pulmonary vascular resistance index were 70.78 ± 19.80 mm Hg and 21.82 ± 11.18 Wood Units·m2, respectively. Patients with CHD-associated PAH experienced a longer diagnostic delay and demonstrated higher pulmonary artery pressure, but better cardiac performance, than those with idiopathic or heritable PAH. An increased number of patients received targeted therapy at the last follow-up compared with baseline. The 5- and 10-year survival rates of the entire cohort were 74.9% and 55.7%, respectively, with better survival in patients with CHD-associated PAH than in those with idiopathic or heritable PAH. Patients with low risk had better survival than those with high risk according to the simplified noninvasive risk score model with weight, function class, and echocardiographic right ventricular size, both at baseline and follow-up. INTERPRETATION: Patients with PPAH in China showed severely compromised hemodynamics with marked diagnostic delay. The long-term survival of PPAH is poor despite the increased usefulness of targeted drugs. The simplified noninvasive risk model demonstrated good performance for predicting survival in Chinese children with PAH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01417338; URL: www. CLINICALTRIALS: gov.

Risk stratification, prognosis, and survival in a pulmonary arterial hypertension cohort in Latin America. A multicenter study.

BACKGROUND: Pulmonary arterial hypertension (PAH) guidelines suggest that achieving a low-risk profile should be the treatment goal. Our aim was to assess a risk assessment strategy based on three non-invasive variables from the ESC/ERS 2015 guidelines in a Latin American cohort. METHODS: 92 incident patients (mean [SD] age 47, 77% female, 53% idiopathic PAH) were included in this retrospective, multicenter study. Patients were stratified at baseline and at early follow-up, within the first year, using three non-invasive variables (WHO functional class, 6-minute walking distance, BNP/NT-proBNP) from the ESC/ERS 2015 risk assessment instrument. Median (IQR) follow-up was 3.11 years (3.01 years). RESULTS: At baseline assessment, 25% of patients were at low risk, 61.9% at intermediate-risk, and 13% at high-risk. At early follow-up (median 9.5 months), 56.5% of patients were at low-risk, 40.2% at intermediate-risk, and 3.2% at high-risk (p<0.001 vs. baseline). According to risk stratification at early follow-up, one, three and five-year overall survival was 100% in the low-risk group (no deaths at five-year follow-up), and 100%, 84% (95% CI: 72-98%), and 66% (95% CI: 48-90%) respectively in the intermediate-risk group, p = 0.0003. Mortality in the high-risk patients at early follow-up was 1/3 (33.3%). One, three, and five-year event-free survival (death or transplant or first hospitalization due to worsening PAH) based on early follow-up risk assessment was higher in the low-risk group, p = 0.0003. CONCLUSION: Our study validates a risk assessment strategy based on three non-invasive variables and confirms that early achievement of a low-risk profile should be the treatment goal.

Risk stratification and response to therapy in patients with pulmonary arterial hypertension and comorbidities: A COMPERA analysis.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities.

Pulmonary arterial hypertension and COVID-19: Piecing the puzzle.

COVID-19 remains a health care concern despite the end of the pandemic. Patients with cardiovascular disease (CVD) are at a higher risk for developing severe COVID-19 complications. Studies investigating the COVID-19 clinical characteristics in pulmonary arterial hypertension (PAH) patients have reported discordant conclusions so far. In this review, we summarize the literature pertaining to the clinical presentation of COVID-19 in patients with PAH. In addition, we discuss common pathological aspects and disease mechanisms between PAH and COVID-19. We present an overview of the different types of PAH-approved therapy and their potential utilization as a treatment in the context of COVID-19. Moreover, we summarize the clinical trials that assessed the safety and efficiency of PAH-approved drugs in COVID-19 patients. Finally, we conclude with proposals for prospective research studies.

The problem of pulmonary arterial hypertension in end-stage renal disease: can peritoneal dialysis be the solution.

BACKGROUND: Pulmonary arterial hypertension (PAH) in the setting of end-stage renal disease (ESRD) has important prognostic and therapeutic consequences. We estimated the prevalence of PAH among patients with ESRD treated with automated peritoneal dialysis (APD), investigated the effect of different variables and compared pulmonary artery pressure and cardiac function at the beginning and end of the study. METHODS: This is a 5-year study in which 31 ESRD patients on APD were recruited after fulfilling inclusion criteria. Blood samples were collected from all patients for the biochemical and hematological data at the beginning of the study and every month and at the study termination. Total body water (TBW) and extracellular water (ECW) were calculated using Watson's and Bird's calculation methods. All patients were followed-up at 3-month interval for cardiac evaluation. Logistic regression analysis was used to assess the relation between different variables and PAH. RESULTS: The mean age of the study population (n = 31) was 51.23 ± 15.24 years. PAH was found in 24.2% of the patients. Mean systolic pulmonary artery pressure (sPAP) and mean pulmonary artery pressure (mPAP) were significantly higher in the APD patients at study initiation than at the end of the study (40.75 + 10.61 vs 23.55 + 9.20 and 29.66 + 11.35 vs 18.24 + 6.75 mmHg respectively, p = 0.001). The median ejection fraction was significantly lower in patients with PAH at zero point than at study termination [31% (27-34) vs 50% (46-52), p = 0.002]. Hypervolemia decreased significantly at the end of study (p <  0.001) and correlated positively with the PAP (r = 0.371 and r = 0.369), p = 0.002). sPAP correlated with left ventricular mass index, hemoglobin level, and duration on APD. CONCLUSIONS: Long term APD (> 1 years) seemed to decrease pulmonary arterial pressure, right atrial pressure and improve left ventricular ejection fraction (LVEF). Risk factors for PAH in ESRD were hypervolemia, abnormal ECHO findings and low hemoglobin levels. Clinical and echocardiographic abnormalities and complications are not uncommon among ESRD patients with PAH. Identification of those patients on transthoracic echocardiography may warrant further attention to treatment with APD.