Fractional exhaled nitric oxide in idiopathic pulmonary arterial hypertension and mixed connective tissue disease complicating pulmonary hypertension.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) has been extensively studied in various causes of pulmonary hypertension (PH), but its utility as a noninvasive marker remains highly debated. The objective of our study was to assess FeNO levels in patients with idiopathic pulmonary arterial hypertension (IPAH) and mixed connective tissue disease complicating pulmonary hypertension (MCTD-PH), and to correlate them with respiratory functional data, disease severity, and cardiopulmonary function. METHODS: We collected data from 54 patients diagnosed with IPAH and 78 patients diagnosed with MCTD-PH at the Shanghai Pulmonary Hospital Affiliated to Tongji University. Our data collection included measurements of brain natriuretic peptide (pro-BNP), cardiopulmonary exercise test (CPET), pulmonary function test (PFT), impulse oscillometry (IOS), and FeNO levels. Additionally, we assessed World Health Organization functional class (WHO-FC) of each patient. RESULTS: (1) The fractional exhaled concentration of nitric oxide was notably higher in patients with IPAH compared to those with MCTD-PH. Furthermore, within the IPAH group, FeNO levels were found to be lower in cases of severe IPAH compared to mild IPAH (P = 0.024); (2) In severe pulmonary hypertension as per the WHO-FC classification, FeNO levels in IPAH exhibited negative correlations with FEV1/FVC (Forced Expiratory Velocity at one second /Forced Vital Capacity), MEF50% (Maximum Expiratory Flow at 50%), MEF25%, and MMEF75/25% (Maximum Mid-expiratory Flow between 75% and 25%), while in severe MCTD-PH, FeNO levels were negatively correlated with R20% (Resistance at 20 Hz); (3) ROC (Receiving operator characteristic curve) analysis indicated that the optimal cutoff value of FeNO for diagnosing severe IPAH was 23ppb; (4) While FeNO levels tend to be negatively correlated with peakPETO2(peak end-tidal partial pressure for oxygen) in severe IPAH, in mild IPAH they had a positive correlation to peakO2/Heart rate (HR). An interesting find was observed in cases of severe MCTD-PH, where FeNO levels were negatively correlated with HR and respiratory exchange ratio (RER), while positively correlated with O2/HR throughout the cardiopulmonary exercise test. CONCLUSION: FeNO levels serve as a non-invasive measure of IPAH severity. Although FeNO levels may not assess the severity of MCTD-PH, their significant makes them a valuable tool when assessing severe MCTD-PH.

Connexin43, A Promising Target to Reduce Cardiac Arrhythmia Burden in Pulmonary Arterial Hypertension.

While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart failure, prognoses and survival rates are much worse in PAH. Patients with PAH are at a higher risk of developing supraventricular arrhythmias and malignant ventricular arrhythmias. The latter underlie sudden cardiac death regardless of the mechanical cardiac dysfunction. Systemic chronic inflammation and oxidative stress are causal factors that increase the risk of the occurrence of cardiac arrhythmias in hypertension. These stressful factors contribute to endothelial dysfunction and arterial pressure overload, resulting in the development of cardiac pro-arrhythmic conditions, including myocardial structural, ion channel and connexin43 (Cx43) channel remodeling and their dysfunction. Myocardial fibrosis appears to be a crucial proarrhythmic substrate linked with myocardial electrical instability due to the downregulation and abnormal topology of electrical coupling protein Cx43. Furthermore, these conditions promote ventricular mechanical dysfunction and heart failure. The treatment algorithm in HTN is superior to PAH, likely due to the paucity of comprehensive pathomechanisms and causal factors for a multitargeted approach in PAH. The intention of this review is to provide information regarding the role of Cx43 in the development of cardiac arrhythmias in hypertensive heart disease. Furthermore, information on the progress of therapy in terms of its cardioprotective and potentially antiarrhythmic effects is included. Specifically, the benefits of sodium glucose co-transporter inhibitors (SGLT2i), as well as sotatercept, pirfenidone, ranolazine, nintedanib, mirabegron and melatonin are discussed. Discovering novel therapeutic and antiarrhythmic strategies may be challenging for further research. Undoubtedly, such research should include protection of the heart from inflammation and oxidative stress, as these are primary pro-arrhythmic factors that jeopardize cardiac Cx43 homeostasis, the integrity of intercalated disk and extracellular matrix, and, thereby, heart function.

Pulmonary Hypertension in Women.

Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by elevated pulmonary artery pressure and increased pulmonary vascular resistance. Females have a higher incidence of PAH, which is reflected globally across registries in the United States, Europe, and Asia. However, despite female predominance, women had better outcomes compared with male patients, a finding that has been labeled the "estrogen paradox." Special considerations should be given to women with PAH regarding sexual health, contraception, family planning, and treatment before, during, and after pregnancy. Pregnant women with PAH should be referred to a pulmonary hypertension care center; a multidisciplinary team approach is recommended, and Cesarean section is the preferred mode of delivery. While pregnancy outcomes have improved over the years with PAH-specific therapy, pregnancy portends a high-risk for those with PAH. Continued research is needed to tailor PAH treatment for women.

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.

Survival and response to pulmonary vasodilator therapies in patients with chronic obstructive pulmonary disease and pulmonary vascular phenotype.

BACKGROUND: The aim of the study was to describe and investigate the effect of pulmonary arterial hypertension (PAH) therapies in a cohort of patients with severe precapillary pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD; PH-COPD), and to assess factors predictive of treatment response and mortality. MATERIAL AND METHODS: We retrospectively included patients with severe incident PH-COPD who received PAH therapy and underwent RHC at diagnosis and on treatment. RESULTS: From 2015 to 2022, 35 severe PH-COPD patients, with clinical features of pulmonary vascular phenotype, were included. Seventeen (48.5%) patients were treated with combined PAH therapy. PAH therapy led to a significant improvement in hemodynamics (PVR -3.5 Wood Units (-39.3%); p < 0.0001), and in the simplified four-strata risk-assessment score, which improved by at least one category in 21 (60%) patients. This effect was more pronounced in patients on dual therapy. Kaplan-Meier estimated survival rates at 1, 3 and 5 years were 94%, 65% and 42% respectively. Univariate analysis showed a significant reduction in survival in patients with a higher simplified risk score at follow-up (Hazard ratio (HR) 2.88 [1.16-7.15]; p = 0.02). Hypoxemia <50 mmHg was correlated to mortality in multivariate analysis (HR 4.33 [1.08-17.42]; p = 0.04). CONCLUSIONS: Our study confirms the poor prognosis of patients with COPD and a pulmonary vascular phenotype and the potential interest of combined PAH therapy in this population, with good tolerability and greater clinical and hemodynamic improvement than monotherapy. Using the simplified risk score during follow-up could be of interest in this population.

Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy.

BACKGROUND: Current guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with cardiopulmonary comorbidities, despite limited available evidence to guide management. RESEARCH QUESTION: Do left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of patients with PAH? STUDY DESIGN AND METHODS: The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial criteria was used to define the phenotype of patients with PAH with risk factors for LHD. Treatment strategy, functional outcome, long-term survival, and risk discrimination were compared with a reference PAH cohort using the Pulmonary Hypertension Society of Australia and New Zealand Registry. RESULTS: A total of 487 incident patients with PAH diagnosed between 2011 and 2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors, with 384 (78.9%) remaining as the reference group. Patients in the PAH with LHD risk factors group were older (66 ± 13 vs 58 ± 19 years; P < .001), had lower pulmonary vascular resistance (393 ± 266 vs 708 ± 391 dyn.s/cm5; P = .031), and had worse 6-min walk distance (286 ± 130 vs 327 ± 136 m; P = .005) at diagnosis. The PAH with LHD risk factors group was less likely to receive initial combination therapy (27% vs 44%; P = .02). Changes in 6-min walk distance at 12 months were similar in both groups (43 ± 77 m in the PAH with LHD risk factors group and 50 ± 90 m in the reference group; P = .50), including when stratified by initial treatment strategy (PAH with LHD risk factors group vs reference PAH group: monotherapy: 40 ± 81 vs 38 ± 95 m, P = .87; combination therapy: 53 ± 78 vs 64 ± 106 m, P = .511). Functional class improvements were also similar in both groups. REVEAL Registry 2.0 risk score effectively discriminated risk in both populations (C statistic = 0.756 for the PAH with LHD risk factors group and C statistic = 0.750 for the reference PAH group). There was no difference in survival between the two groups (log-rank test, P = .29). INTERPRETATION: In a real-world cohort, patients with PAH with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected patients with PAH with LHD risk factors who were treated with initial combination therapy derived similar functional response compared with the reference group. Further studies are needed to phenotype patients with PAH with cardiopulmonary comorbidities who may benefit from initial combination therapy.

Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

Anti-survival motor neuron complex antibodies as a novel biomarker for pulmonary arterial hypertension and interstitial lung disease in mixed connective tissue disease.

OBJECTIVE: The presence of anti-U1 RNP antibodies (Abs) is critical for diagnosing MCTD. The aim of this study is to evaluate the clinical relevance of anti-survival motor neuron (SMN) complex Abs, which often coexist with anti-U1 RNP Abs. METHODS: A total of 158 newly diagnosed consecutive cases of SLE, SSc or MCTD with anti-U1 RNP Abs were enrolled in this multicentre observational study between April 2014 and August 2022. Serum anti-SMN complex Abs were screened by immunoprecipitation of 35S-methionine-labelled cell extracts, and associations between anti-SMN complex Abs positivity and clinical characteristics were analysed. RESULTS: Anti-SMN complex Abs were detected in 36% of MCTD patients, which was significantly higher than that in SLE (8%) or SSc (12%). Among MCTD patients classified based on the combination of the clinical features of SLE, SSc and idiopathic inflammatory myopathies, anti-SMN complex Abs showed the highest prevalence in a subset with clinical features of all three components. Anti-SMN complex Abs-positive MCTD had a higher prevalence of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), which are related to poor prognosis, than negative patients. Moreover, all three cases of death within 1 year of the treatment were positive for anti-SMN complex Abs. CONCLUSIONS: Anti-SMN complex Abs is the first biomarker of a typical subset of MCTD which bears organ damages such as PAH and ILD.

Comprehensive imaging in patients with suspected pulmonary arterial hypertension.

Currently, several imaging techniques are being used for a comprehensive evaluation of patients with suspected pulmonary hypertension (PH), in order to provide information that may clarify the presence and identify the aetiology of this complex pathology. The current paper is focused on recent updates regarding the importance of comprehensive imaging techniques for patients with suspected PH. Transthoracic echocardiography that can mainly detect right ventricle pressure overload and dysfunction is the cornerstone of imaging evaluation, while right heart catheterisation remains the gold standard assessment method. Chest radiography that may exclude pleuroparenchymal lung diseases, CT, the primary imaging modality for the assessment of lung parenchyma and CT pulmonary angiography, that allows for the non-invasive assessment of the pulmonary arteries, are equally important. Imaging techniques like dual-energy CT, single photon emission CT and ventilation perfusion scan may provide accurate diagnostic information for patients with chronic thromboembolic PH. Cardiac MRI provides the most accurate three-dimensional characterisation of the right ventricle. Accurate use of diagnostic imaging algorithms allows early detection of the disease, with the constant goal of improved PH patients prognosis.

Impact of Systemic Sclerosis-Associated Interstitial Lung Disease With and Without Pulmonary Hypertension on Survival: A Large Cohort Study of the German Network for Systemic Sclerosis.

BACKGROUND: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis. RESEARCH QUESTION: Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact? STUDY DESIGN AND METHODS: Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival. RESULTS: Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk. INTERPRETATION: ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival.

Association of delayed diagnosis of pulmonary arterial hypertension with its prognosis.

BACKGROUND: Currently, pulmonary hypertension-targeted therapy has been shown to improve the survival of patients with pulmonary artery hypertension (PAH). However, the importance of early diagnosis has not been investigated. Therefore, this study aimed to investigate whether a delayed diagnosis of PAH is associated with its prognosis. METHODS AND RESULTS: A total of 66 consecutive untreated patients were diagnosed with PAH from January 2008 to December 2021 at the Kagoshima University Hospital. The time from symptom onset to diagnosis correlated with brain natriuretic peptide levels (p < 0.001), right ventricle (RV) Tei index (p < 0.001), and the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio (p = 0.003). These findings suggest that in patients with PAH, RV function declines with increasing time from symptom onset to diagnosis. Furthermore, older patients with PAH appeared to have a longer time from symptom onset to diagnosis. Next, patients were divided into delayed diagnosis (>3 months) and early diagnosis (≤3 months) groups based on the time from symptom onset to diagnosis. Patients were categorized into three groups according to the European Society of Cardiology (or the European Respiratory Society) risk stratification guidelines. Patients diagnosed with PAH within 3 months of symptom onset were significantly in the low- or intermediate-risk groups (p < 0.001). A Kaplan-Meier analysis revealed that the cumulative event-free rate was significantly lower (p < 0.01) in the delayed diagnosis group than in the early diagnosis group. A delayed diagnosis was significantly associated with a worse outcome than an early diagnosis, after adjusting for different sets of confounding factors. CONCLUSIONS: A delayed PAH diagnosis is associated with a poor prognosis. Early diagnosis of PAH may lead to a low-risk treatment. Furthermore, older patients need more careful screening for PAH.

Triple vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease.

OBJECTIVE: This study assessed the long-term effects of triple therapy with prostanoids on patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), as there is limited information on the safety and efficacy of this treatment approach. METHODS: A retrospective cohort study was conducted on patients with PAH-CHD who were actively followed up at our centre. All patients were already receiving dual combination therapy at maximum doses. Clinical characteristics, including functional class (FC), 6-minute walking test distance (6MWTD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, were documented before initiating triple therapy and annually for a 2-year follow-up period. RESULTS: A total of 60 patients were included in the study, with a median age of 41 years and 68% being women. Of these, 32 had Eisenmenger syndrome, 9 had coincidental shunts, 18 had postoperative PAH and 1 had a significant left-to-right shunt. After 1 year of triple combination initiation, a significant improvement in 6MWTD was observed (406 vs 450; p=0.0027), which was maintained at the 2-year follow-up. FC improved in 79% of patients at 1 year and remained stable in 76% at 2 years. NT-proBNP levels decreased significantly by 2 years, with an average reduction of 199 ng/L. Side effects were experienced by 33.3% of patients but were mostly mild and manageable. Subgroup analysis showed greater benefits in patients without Eisenmenger syndrome and those with pre-tricuspid defects. CONCLUSIONS: Triple therapy with prostanoids is safe and effective for patients with PAH-CHD, improving FC, 6MWTD and NT-proBNP levels over 2 years. The treatment is particularly beneficial for patients with pre-tricuspid defects and non-Eisenmenger PAH-CHD.

Efficacy and safety of iloprost in the treatment of pulmonary arterial hypertension: A systematic review and meta-analysis.

BACKGROUND: The efficacy of iloprost in treating pulmonary arterial hypertension (PAH) is controversial. Adverse reactions such as hypotension may occur during treatment. OBJECTIVES: Aim to evaluate the efficacy and safety of iloprost for PAH. METHODS: Studies were obtained from an electronic search of the CNKI, Wanfang, VIP, SinoMed, PubMed, Medline, Embase, and Cochrane Library databases up to May 18, 2023. A meta-analysis of each study was performed using RevMan 5.4 with a 95 % confidence interval (CI). A randomized or fixed-effects model was applied according to a heterogeneity test. RESULTS: Twelve trials involving 718 participants were selected, including 433 in five randomized controlled trials (RCTs) and 285 in seven prospective clinical trials. All the patients received iloprost inhalation. The short- and prolonged treatment groups significantly improved the 6-minute walking distance (6 MWD). The mortality and clinical deterioration incidences in the iloprost group were not significantly different from those in the control group. The mean pulmonary arterial pressure (mPAP) was reduced after 3 months of iloprost RCTs and 12 months of prospective treatment. Iloprost decreased pulmonary vascular resistance (PVR) by approximately 231.29 units, significantly increased cardiac output (CO), and improved the quality of life (QoL). The main adverse reactions to iloprost treatment were cough (17 %), headache (16.4 %), and flushing (12.4 %). CONCLUSION: Iloprost, either used alone or as adjuvant therapy, can enhance exercise capacity, lower hemodynamic parameters, and improve long-term outcomes. However, the risk of mortality and clinical deterioration remains unknown.

Schistosomiasis: A neglected cause of pulmonary arterial hypertension in Brazil.

Schistosomiasis is a prevalent disease in Brazil whose etiological agent is Schistosoma mansoni, the main species associated with pulmonary arterial hypertension (PAH), a serious complication. It is estimated that this complication affects up to 15% of patients with the hepatosplenic form of the disease. Despite being an endemic country, Brazil does not have a screening scheme for cases of PAH associated with schistosomiasis (PAH-Sch), nor protocols for notification and treatment of this vascular complication. The objectives of this literature review are to gather knowledge about the pathophysiology, clinical manifestations, diagnosis and treatment of PAH-Sch and to highlight relevant aspects for the Brazilian reality. The pathophysiology, although lacking information, has proliferative vasculopathy as a central element. The clinical presentation of this disease can be asymptomatic or with nonspecific manifestations. Thus, complementary exams are essential for a confirmatory diagnosis, the gold standard being right heart catheterization, a scarce resource in endemic regions of the country. The treatment of PAH-Sch is similar to that performed for other causes of PAH, but the impact of anthelmintic therapy on the evolution of the vascular pathology is unknown. Therefore, Brazil needs to develop a screening plan for early diagnosis of PAH-Sch and new studies should be carried out to determine a more specific treatment.

Evaluation of maternal-fetal outcomes in pregnancy complicated with severe pulmonary hypertension and its influencing factors: a single-center retrospective study in China.

OBJECTIVE: Pregnancy is not recommended for patients with severe pulmonary hypertension (PH) due to the significant risks it poses to both the mother and fetus. The objective of this study is to describe the maternal-fetal outcomes in pregnant women with PH and identify the factors that influence these outcomes. METHOD: This retrospective study analyzed clinical data from 25 patients with severe PH who were admitted to our hospital between January 2018 and December 2022. The data we used came from a public general hospital in Fujian Province. RESULTS: The mean systolic pulmonary artery pressure (sPAP) of 25 patients was 105.12 ± 22.70 mmHg. All patients had received one or more multidisciplinary team (MDT) treatments before terminating their pregnancies. Among the pregnant women, four experienced a pulmonary hypertensive crisis (PHC), seven had heart failure, and one had postpartum hemorrhage (PPH). Among them, seven (28%) pregnant women died primarily due to heart failure and PHC. Among the fetal outcomes, twelve resulted in therapeutic abortion, and eleven resulted in preterm birth. Among the perinatal complications, eleven infants (84.6%) were born prematurely, six infants (46.2%) experienced neonatal asphyxia, eight infants (61.5%) had low birth weight, and two infants (15.4%) died during the perinatal period. According to the etiology, seven individuals had idiopathic pulmonary arterial hypertension (iPAH), ten had pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH), six had pulmonary hypertension associated with left heart disease (LDH-PH), and two had pulmonary arterial hypertension caused by other diseases (oPAH). The sPAP levels of iPAH and CHD-PAH were significantly higher than those of LDH-PH and oPAH (p < 0.05). Additionally, the gestational weeks of LDH-PH were higher than those of iPAH (p < 0.05). The number of patients with New York Heart Association (NYHA) heart function grade III-V was higher in the death group compared to the non-death group (p < 0.05). CONCLUSION: Pregnancy in women with severe PH carries a high risk of mortality. Therefore, contraception is strongly recommended for these women. NYHA cardiac function grade III-IV was useful in predicting the risk of mortality.

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.

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

BACKGROUND: To investigate the risk factors for the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE). METHODS: The literature related to risk factors for the development of PAH in SLE patients was searched by the computer on China national knowledge infrastructure (CNKI), PubMed, and Embase, and the literature search was limited to the period of library construction to October 2022. Two researchers independently performed literature screening and literature information extracting, including first author, publication time, case collection time, sample size, and study factors, and used the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the literature. The relationship between each clinical manifestation and laboratory index and the occurrence of PAH in SLE patients was evaluated based on the ratio (OR value) and its 95% CI. RESULTS: A total of 24 publications were included, including 23 case-control studies and 1 cohort study with NOS ≥ 6, and the overall quality of the literature was high. The risk of PAH was higher in SLE patients who developed Raynaud phenomenon than in those who did not [OR = 2.39, 95% CI (1.91, 2.99), P < .05]; the risk of PAH was higher in SLE patients who were positive for anti-RNP antibodies than in those who were negative for anti-RNP antibodies [OR = 1.77, 95% CI (1.17, 3.2.65), P < .05]; the risk of PAH was higher in SLE patients with interstitial lung lesions than in those without combined interstitial lung lesions [OR = 3.28, 95% CI (2.37, 4.53), P < .05]; the risk of PAH was higher in SLE patients with combined serositis than in those without serositis [OR = 2.28, 95% CI (1.83, 2.84), P < .05]. The risk of PAH was higher in SLE patients with combined pericardial effusion than in those without pericardial effusion [OR = 2.97, 95% CI (2.37, 3.72), P < .05]; the risk of PAH was higher in SLE patients with combined vasculitis than in those without vasculitis [OR = 1.50, 95% CI (1.08, 2.07), P < .05]; rheumatoid factor-positive SLE patients had a higher risk of PAH than those with rheumatoid factor-negative [OR = 1.66, 95% CI (1.24, 2.24), P < .05]. CONCLUSION: Raynaud phenomenon, vasculitis, anti-RNP antibodies, serositis, interstitial lung lesions, rheumatoid factor, and pericardial effusion are risk factors for the development of PAH in patients with SLE.

Cutaneous polyarteritis nodosa and pulmonary arterial hypertension: An unexpected liaison. A case report.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a form of medium-sized vessel necrotizing vasculitis. It is a rare, skin-limited variant of polyarteritis nodosa, characterized by dermal and subcutaneous tissue involvement. The most common findings in cPAN include digital gangrene, livedo reticularis, and tender subcutaneous nodules. However, while limited to the skin, cPAN results in significant morbidity and mortality due to the accompanying skin ischemia and necrosis, such that patients are vulnerable to superinfection. Here, we describe a unique presentation of cPAN associated with pulmonary arterial hypertension (PAH). METHODS: A 78-year-old female presented with digital ischemia and leg ulcers associated with PAH. Skin biopsy showed necrotizing fibrinoid necrosis of the small- and middle-sized vessels of the dermis. A diagnosis of cPAN and PAH was made. The patient was treated with glucocorticoids, vasodilators, and cyclophosphamide. RESULTS: She died due to severe sepsis complications. CONCLUSION: To date, this is the first case report describing the association between cPAN and PAH. In this case, PAH is a complication of the cutaneous vasculitides suggesting that vasculopathy could play a role in the pathophysiology of PAH. However, the underlying pathophysiological mechanisms still have to be firmly established.

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

BACKGROUND: 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. OBJECTIVE: To assess the long-term impact of sequential triple combination therapy in patients with PAH who are not at goal on dual combination therapy. STUDY DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSION: Add-on sequential triple combination therapy significantly increased functional, echocardiographic, and hemodynamic parameters with improvement in risk category and survival.