Pulmonary Arterial Hypertension with Features of Venous Involvement: A Detective's Task. / Hipertensão Arterial Pulmonar com Características de Envolvimento Venoso: Um Trabalho Investigativo.

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis are rare types of histopathological substrates within the spectrum of pulmonary arterial hypertension (PAH) with a very poor prognosis. They are characterized by a widespread fibroproliferative process of the small caliber veins and/or capillaries with sparing of the larger veins, resulting in a pre-capillary pulmonary hypertension phenotype. Clinical presentation is unspecific and similar to other PAH etiologies. Definitive diagnosis is obtained through histological analysis, although lung biopsy is not advised due to a higher risk of complications. However, some additional findings may allow a presumptive clinical diagnosis of PVOD, particularly a history of smoking, chemotherapy drug use, exposure to organic solvents (particularly trichloroethylene), low diffusing capacity for carbon monoxide (DLCO), exercise induced desaturation, and evidence of venous congestion without left heart disease on imaging, manifested by a classical triad of ground glass opacities, septal lines, and lymphadenopathies. Lung transplant is the only effective treatment, and patients should be referred at the time of diagnosis due to the rapid progression of the disease and associated poor prognosis. We present a case of a 58-year-old man with PAH with features of venous/capillary involvement in which clinical suspicion, prompt diagnosis, and early referral for lung transplantation were determinant factors for the successful outcome.

A doença veno-oclusiva pulmonar (DVOP) e a hemangiomatose capilar pulmonar são tipos raros de substratos histopatológicos dentro do espectro da hipertensão arterial pulmonar (HAP) com prognóstico muito ruim. Caracterizam-se por um processo fibroproliferativo generalizado das veias e/ou capilares de pequeno calibre com preservação das veias maiores, resultando em um fenótipo de hipertensão pulmonar pré-capilar. A apresentação clínica é inespecífica e semelhante a outras etiologias de HAP. O diagnóstico definitivo é obtido por meio de análise histológica, embora a biópsia pulmonar não seja aconselhada devido ao maior risco de complicações. No entanto, alguns achados adicionais podem permitir um diagnóstico clínico presuntivo de DVOP, especialmente história de tabagismo, uso de drogas quimioterápicas, exposição a solventes orgânicos (particularmente tricloroetileno), baixa capacidade de difusão do monóxido de carbono (DLCO), dessaturação ao esforço e evidências de doença venosa sem doença cardíaca esquerda no exame de imagem, manifestada por uma tríade clássica de opacidades em vidro fosco, linhas septais, e linfadenopatias. O transplante pulmonar é o único tratamento eficaz e os pacientes devem ser encaminhados no momento do diagnóstico, devido à rápida progressão da doença e ao prognóstico ruim. Apresentamos o caso de um homem de 58 anos com HAP com características de envolvimento venoso/capilar em que a suspeita clínica, o pronto diagnóstico e o encaminhamento precoce para transplante pulmonar foram determinantes para um bom desfecho.

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again.

Systemic sclerosis (SSc) is a heterogeneous disease characterized by autoimmunity, vasculopathy, and fibrosis which affects the skin and internal organs. One key aspect of SSc vasculopathy is pulmonary arterial hypertension (SSc-PAH) which represents a leading cause of morbidity and mortality in patients with SSc. The pathogenesis of pulmonary hypertension is complex, with multiple vascular cell types, inflammation, and intracellular signaling pathways contributing to vascular pathology and remodeling. In this review, we focus on shared molecular features of pulmonary hypertension and those which make SSc-PAH a unique entity. We highlight advances in the understanding of the clinical and translational science pertinent to this disease. We first review clinical presentations and phenotypes, pathology, and novel biomarkers, and then highlight relevant animal models, key cellular and molecular pathways in pathogenesis, and explore emerging treatment strategies in SSc-PAH.

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Pulmonary arterial hypertension (PAH) is a severe disease characterized by abnormal pulmonary vascular remodeling and increased right ventricular pressure load, posing a significant threat to patient health. While some pathological mechanisms of PAH have been revealed, the deeper mechanisms of pathogenesis remain to be elucidated. In recent years, bioinformatics has provided a powerful tool for a deeper understanding of the complex mechanisms of PAH through the integration of techniques such as multi-omics analysis, artificial intelligence, and Mendelian randomization. This review focuses on the bioinformatics methods and technologies used in PAH research, summarizing their current applications in the study of disease mechanisms, diagnosis, and prognosis assessment. Additionally, it analyzes the existing challenges faced by bioinformatics and its potential applications in the clinical and basic research fields of PAH in the future.

Eye signs as a novel risk predictor in pulmonary arterial hypertension associated with systemic lupus erythematosus.

OBJECTIVE: To investigate the role of eye signs in predicting poor outcomes in systemic lupus erythematosus (SLE) patients with pulmonary arterial hypertension (PAH). METHODS: This prospective observational study recruited patients diagnosed with SLE-PAH from Jan. 2021 to Dec. 2021 at the First Affiliated Hospital of Nanchang University; those with other potential causes of PAH were excluded. The evaluation of various parameters, such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walking distance (6MWD), World Health Organization functional class (WHO-FC), echocardiography, and risk stratification based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines, was conducted at intervals of every 1-3 months, and a 6-month follow-up period was observed. The primary outcome measure considered improvement if there was a decline in the risk stratification grade at the end point and unimproved if there was no decline. Conjunctival microvascular images were observed and recorded. RESULTS: A total of 29 SLE-PAH patients were enrolled, comprising 12 in the improved group and 17 in the nonimproved group. All SLE-PAH patients showed various manifestations of eye signs, including vessel twisting, dilation, ischaemic areas, haemorrhages, reticulum deformity, and wound spots. The nonimproved group exhibited significantly lower vessel density (VD) and microvascular flow index (MFI) of conjunctival microvascular images than the improved group. Correlation analysis revealed that VD displayed a negative correlation with the WHO-FC (r = -0.413, p = 0.026) and NT-proBNP (r = -0.472, p = 0.010), as well as a positive correlation with the 6MWD (r = 0.561, p = 0.002). Similarly, MFI exhibited a negative correlation with WHO-FC (r = -0.408, p = 0.028) and NT-proBNP (r = -0.472, p = 0.010) and a positive correlation with 6MWD (r = 0.157, p = 0.004). Multivariate logistic regression analysis indicated that VD (OR 10.11, 95% CI 1.95-52.36), MFI (OR 7.85, 95% CI 1.73-35.67), NT-proBNP, and 6MWD were influential factors in predicting the prognostic improvement of SLE-PAH patients. ROC curve analysis demonstrated that VD, MFI, 6MWD, and NT-proBNP (with respective AUC values of 0.83, 0.83, 0.76, and 0.90, respectively) possessed a sensitivity and specificity of 75 and 100%, as well as 83 and 100%, respectively. Regarding prognostic prediction, VD and MFI exhibited higher sensitivity than 6MWD, whereas MFI displayed higher sensitivity and specificity than NT-proBNP. CONCLUSION: SLE-PAH can lead to various conjunctival microvascular manifestations in which vascular density and microvascular flow index can be used to assess cardiopulmonary function and predict therapeutic efficacy and prognosis in SLE-PAH patients.

Idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH): Similarities, differences and the role of autoimmunity.

Pre-capillary pulmonary arterial hypertension (PAH) is hemodynamically characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) > 2. PAH is classified in six clinical subgroups, including idiopathic PAH (IPAH) and PAH associated to connective tissue diseases (CTD-PAH), that will be the main object of this review. The aim is to compare these two PAH subgroups in terms of epidemiology, histological and pathogenic findings in an attempt to define disease-specific features, including autoimmunity, that may explain the heterogeneity of response to therapy between IPAH and CTD-PAH.

Radiofrequency catheter ablation for pulmonary hypertension patients with atrial flutter.

AIMS: We aimed to evaluate the effects of radiofrequency catheter ablation (RFCA) and the factors influencing mortality after RFCA in patients with pulmonary hypertension (PH) and atrial flutter (AFL). METHODS AND RESULTS: Fifty-eight consecutive PH patients with AFL who underwent an electrophysiological study and RFCA between April 2013 and August 2021 were selected for this study. In the study population, pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) was the most common type of PH (n = 34, 59%), followed by idiopathic pulmonary arterial hypertension (IPAH) (n = 19, 33%). Typical atrial flutter was the most common type of atrial flutter (n = 50, 86.2%). Sinus rhythm was restored in 53 (91.4%) patients during RFCA. After a mean follow-up of 33.8 months, AFL recurred in a total of 22 patients. Nine of them underwent repeat RFCA, and the site of the repeat ablation was not exactly the same as the first. At a median follow-up of 34.6 months after the last ablation, none of the patients who underwent repeat RFCA experienced AFL recurrence, and all of these patients survived. There were no procedure-related complications during hospitalization or follow-up. Univariate Cox regression analysis suggested that AFL recurrence after the last ablation was not associated with all-cause mortality. NT-proBNP (HR: 1.00024, 95% CI: 1.00008-1.00041, P = 0.004), pulmonary artery systolic pressure (PASP) (HR: 1.048, 95% CI: 1.020-1.076, P = 0.001), and IPAH (vs. PAH-CHD, HR: 7.720, 95% CI: 1.437-41.483, P = 0.017) were independent predictors of all-cause mortality in PH patients with AFL after RFCA. Receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of PASP for predicting all-cause mortality was 0.708. There was no significant difference in the Kaplan-Meier curves for all-cause mortality between patients with AFL recurrence after the last ablation and those without recurrence (P = 0.851). Patients with higher PASP (≥110 mmHg) and IPAH showed the lower survival rate in Kaplan-Meier curves. CONCLUSION: Repeat ablation was safe and feasible in patients with recurrent AFL and can maintain sinus rhythm. AFL recurrence was not associated with all-cause mortality, and patients with high PASP or IPAH were at higher risk for adverse outcomes.

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.

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.

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.

A Meta-Analysis of Atrial Septal Defect Closure in Patients With Severe Pulmonary Hypertension: Is There a Room for Poking Holes Amid Debate?

Severe pulmonary arterial hypertension (PAH) associated with atrial septal defect (ASD) poses a challenge to a closure of ASD, particularly severe PAH that persists even after pharmacological therapeutic strategy. Our study was aimed to evaluate this matter. A systematic literature search from several databases was conducted up until August 1st, 2023. A meta-analysis was undertaken on studies that reported hemodynamic measurements in ASD patients with severe PAH before and after closure. The primary objectives were the extent of improvement in all hemodynamic parameters following closure, and the secondary outcomes were major adverse cardiac events (MACEs) during follow-up. Our study comprised 10 studies with a total of 207 participants. Patients were divided into treat-and-repair and straight-to-repair groups based on the therapeutic strategy. Meta-analysis of all studies demonstrated significant improvement in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), pulmonary vascular resistance index (PVRI), 6-minutes walking distance (6MWD), and lower prevalence of World Health Organization functional classes (WHO fc), particularly in the treat-and-repair strategy subgroup. Additionally, merely 4 of the 156 individuals died from cardiac causes, and only 1 required rehospitalization, indicating a low likelihood of MACEs arising. Our new findings support the notion that effective shunt closure can improve various hemodynamic parameters in carefully chosen patients with noncorrectable ASD-PAH. Further large and prospective observational studies are still warranted to validate these findings.

An editorial regarding the article 'A meta-analysis of atrial septal defect closure in patients with severe pulmonary hypertension: is there a room for poking holes amidst debate?'

Pulmonary arterial hypertension (PAH) related to an atrial septal defect (ASD) poses a challenge to transcatheter closure of an ASD. In patients with untreated ASDs, chronic pulmonary over-circulation due to shunt flow can cause pulmonary vascular remodeling and increased pulmonary vascular resistance. PAH is one of the difficult situations to treat. Complex pathophysiology, association of the multiple comorbidities make clinical scenario challenging. The closure of ASD in patients with PAH improves PAH severity and cardiac functional capacity and reduces atrial arrhythmias. However, some patients show remaining PAH or aggravation of PAH post-ASD closure. PAH is a strong predictor of mortality in older patients who undergo ASD closure. Hence, the decision to opt for ASD closure should be carefully considered in high-risk patients with PAH. As per the American Heart Association/American College of Cardiology 2018 guidelines, ASD with elevated pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) more than two-thirds systemic is considered to be a contraindication for closure. However, it is difficult to determine the outcomes for ASD closure in patients with moderately-to-severely elevated PVR. A "treat and repair strategy" might be an option. In addition, the patient should be carefully selected by the observation of PVR change through vasoreactivity and balloon occlusion tests, and then closure should be considered. For patients with a predictable poor prognosis, research on the risk assessment of ASD closure in patients with PAH will be needed for a more individualized treatment plan.

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.

Schistosomiasis-associated pulmonary hypertension unveils disrupted murine gut-lung microbiome and reduced endoprotective Caveolin-1/BMPR2 expression.

Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic S. mansoni infection that can lead to heart failure and death. During PAH, the expansion of apoptosis-resistant endothelial cells (ECs) has been extensively reported; however, therapeutic approaches to prevent the progression or reversal of this pathological phenotype remain clinically challenging. Previously, we showed that depletion of the anti-apoptotic protein Caveolin-1 (Cav-1) by shedding extracellular vesicles contributes to shifting endoprotective bone morphogenetic protein receptor 2 (BMPR2) towards transforming growth factor beta (TGF-ß)-mediated survival of an abnormal EC phenotype. However, the mechanism underlying the reduced endoprotection in PAH remains unclear. Interestingly, recent findings indicate that, similar to the gut, healthy human lungs are populated by diverse microbiota, and their composition depends significantly on intrinsic and extrinsic host factors, including infection. Despite the current knowledge that the disruption of the gut microbiome contributes to the development of PAH, the role of the lung microbiome remains unclear. Thus, using a preclinical animal model of Sch-PAH, we tested whether S. mansoni infection alters the gut-lung microbiome composition and causes EC injury, initiating the expansion of an abnormal EC phenotype observed in PAH. Indeed, in vivo stimulation with S. mansoni eggs significantly altered the gut-lung microbiome profile, in addition to promoting injury to the lung vasculature, characterized by increased apoptotic markers and loss of endoprotective expression of lung Cav-1 and BMPR2. Moreover, S. mansoni egg stimulus induced severe pulmonary vascular remodeling, leading to elevated right ventricular systolic pressure and hypertrophy, characteristic of PAH. In vitro, exposure to the immunodominant S. mansoni egg antigen p40 activated TLR4/CD14-mediated transient phosphorylation of Cav-1 at Tyr14 in human lung microvascular EC (HMVEC-L), culminating in a mild reduction of Cav-1 expression, but failed to promote death and shedding of extracellular vesicles observed in vivo. Altogether, these data suggest that disruption of the host-associated gut-lung microbiota may be essential for the emergence and expansion of the abnormal lung endothelial phenotype observed in PAH, in addition to S. mansoni eggs and antigens.

Canagliflozin ameliorates hypobaric hypoxia-induced pulmonary arterial hypertension by inhibiting pulmonary arterial smooth muscle cell proliferation.

Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary vascular resistance, and right ventricular failure. Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is originally used in diabetes patients which could assist the glucose excretion and decrease blood glucose. Recently, a few studies have reported the protective effect of SGLT2 inhibitor on monocrotaline-induced PAH. However, the effects of canagliflozin on hypobaric hypoxia-induced PAH as well as its mechanism still unclear. In this study, we used hypobaric hypoxia-induced PAH mice model to demonstrate if canagliflozin could alleviate PAH and prevent pulmonary vessel remodeling. We found that daily canagliflozin administration significantly improved survival in mice with hypobaric hypoxia-induced PAH compared to vehicle control. Canagliflozin treatment significantly reduced right ventricular systolic pressure and increased pulmonary acceleration time determined by hemodynamic assessments. Canagliflozin significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles compared to vehicle treated mice. In addition, canagliflozin inhibited the proliferation and migration of pulmonary arterial smooth muscle cells through suppressing glycolysis and reactivating AMP-activated protein kinase signaling pathway under hypoxia condition. In summary, our findings suggest that canagliflozin is sufficient to inhibit pulmonary arterial remodeling which is a potential therapeutic strategy for PAH treatment.

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.

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.

Scleroderma pulmonary arterial hypertension: the same as idiopathic pulmonary arterial hypertension?

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc), which confers significant morbidity and mortality. The current therapies and treatment strategies for SSc-associated PAH (SSc-PAH) are informed by those used to treat patients with idiopathic PAH (IPAH). There are, however, important differences between these two diseases that impact diagnosis, treatment, and outcomes. RECENT FINDINGS: Both SSc-PAH and IPAH are incompletely understood with ongoing research into the underlying cellular biology that characterize and differentiate the two diseases. Additional research seeks to improve identification among SSc patients in order to diagnose patients earlier in the course of their disease. Novel therapies specifically for SSc-PAH such as rituximab and dimethyl fumarate are under investigation. SUMMARY: Although patients with SSc-PAH and IPAH present with similar symptoms, there are significant differences between these two forms of PAH that warrant further investigation and characterization of optimal detection strategies, treatment algorithms, and outcomes assessment.