Cause Of Pulmonary Arterial Hypertension Research Articles

Novel echocardiographic parameters in pulmonary hypertension assessment and the relationship between echocardiography and 6-minute walking test.

Pulmonary artery stiffness (PAS) has been shown to be related to pulmonary artery pressure in patients with pulmonary artery hypertension (PAH). The aim of this study was to determine the correlation between functional capacity and echocardiographic indices of PAS in patients with PAH. This cross-sectional study was performed on patients with PAH who were confirmed by right heart catheterization and referred to Imam Reza PAH clinic for routine follow-up between November 2019 and January 2020. All patients underwent echocardiography and the maximum Doppler frequency shift, pulmonary acceleration time, peak velocity of the pulmonary flow, and velocity time integral, as well as PAS, were measured. All patients performed a 6-minute walk test. Fifty patients with a mean age of 41.90 ± 14.73 years old participated in this study. The majority of the patients were female (74%). The most common cause of PAH was idiopathic (74%). There was a significant correlation between PAS and pulmonary artery systolic pressure (r = 0.302, P = .041), second pulmonary valve pulse Doppler velocity (V2) (r = -0.461, P = .003), time from onset of pulmonary flow ejection to V2/first pulmonary valve pulse Doppler velocity (r = -0.311, P = .037) and Z3 ratio (r = -0.346, P = .023). There was no significant correlation between PAS and 6-minute walk test, pulmonary vascular resistance, and tricuspid annular plane systolic excursion (P > .05). There was a significant correlation between V2 and pulmonary vascular resistance (r = 0.359, P = .049). PAS and first pulmonary valve pulse Doppler velocity are simple, noninvasive, available tools for the evaluation of pulmonary vascular beds and diagnosis of presymptomatic clinical status in patients with PAH.

Hydroxy-Safflower Yellow A Mitigates Vascular Remodeling in Rat Pulmonary Arterial Hypertension.

The underlying causes of pulmonary arterial hypertension (PAH) often remain obscure. Addressing PAH with effective treatments presents a formidable challenge. Studies have shown that Hydroxysafflor yellow A (HSYA) has a potential role in PAH, While the mechanism underlies its protective role is still unclear. The study was conducted to investigate the potential mechanisms of the protective effects of HSYA. Using databases such as PharmMapper and GeneCards, we identified active components of HSYA and associated PAH targets, pinpointed intersecting genes, and constructed a protein-protein interaction (PPI) network. Core targets were singled out using Cytoscape for the development of a model illustrating drug-component-target-disease interactions. Intersection targets underwent analysis for Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Selected components were then modeled for target interaction using Autodock and Pymol. In vivo validation in a monocrotaline-induced PAH (MCT-PAH) animal model was utilized to substantiate the predictions made by network pharmacology. We associated HSYA with 113 targets, and PAH with 1737 targets, identifying 34 mutual targets for treatment by HSYA. HSYA predominantly affects 9 core targets. Molecular docking unveiled hydrogen bond interactions between HSYA and several PAH-related proteins such as ANXA5, EGFR, SRC, PPARG, PGR, and ESR1. Utilizing network pharmacology and molecular docking approaches, we investigated potential targets and relevant human disease pathways implicating HSYA in PAH therapy, such as the chemical carcinogenesis receptor activation pathway and the cancer pathway. Our findings were corroborated by the efficacious use of HSYA in an MCT-induced rat PAH model, confirming its therapeutic potential.

Modelling and Docking studies of Endothelin receptors ( PAH Inducing proteins) with Bosenten Monohydrate

Pulmonary arterial hypertension (PAH) is a serious disease of pulmonary arteries. When Pulmonary Arterial Hypertension (PAH) develops, blood flow through the pulmonary arteries is restricted and the right side of the heart is put under increasing strain to pump blood through to the lungs. The different changes in the blood vessels raise the pressure and increase the resistance to blood flow through the lungs, making it harder for the heart to pump blood through the lungs. Over time, due to the additional strain, the heart begins to work less effectively and eventually, the right heart can fail (this is known as 'right ventricular failure'). Pulmonary arterial hypertension (PAH) is relatively rare. It is estimated that there are about 30-50 people with PAH for every million of the population. While Pulmonary Arterial Hypertension (PAH) can occur at any age, it is more common in women in their childbearing years and the average age of diagnosis is 36. The exact cause of pulmonary arterial hypertension (PAH) remains unknown. In recent years research has focused particularly on the role of three specific substances that are produced in these cells: prostacyclin, nitric oxide and endothelin. These three agents work together to help the blood to flow smoothly through the heart and lungs and it is thought that an imbalance in levels of one or more of these substances contributes to the development of conditions such as Pulmonary Arterial Hypertension (PAH). This leads to the progressive changes in the vessels and the subsequent rise in pressure. This area of research has led to the development of specific treatments for Pulmonary Arterial Hypertension (PAH).

To estimate prevalence of pulmonary arterial hypertension in HIV patients and its association with CD4 cell count

IntroductionHIV infection is considered as one of the leading infectious cause of pulmonary arterial hypertension (PAH) and it exhibits higher rate of development of this condition than general population. The prevalence of HIV associated PAH has not been established accurately and varies based on factors such as geographical distribution, gender, duration of HIV and ART etc. This study aims to estimate the prevalence of PAH in HIV infected patients who are on first line ART and to study the association of PAH with CD4 count and viral load. MethodsThis cross-sectional study was conducted on 150 HIV positive patients who visited medical OPD and ART centre, JLN medical college and hospital, Ajmer and were above 18 years of age and were on first line ART. PAH was identified through transthoracic doppler echocardiographic screening and systolic pulmonary artery pressure (sPAP) estimation of more than 35 mmHg was used to diagnose PAH. ResultIn this study, out of 150 patients, PAH was diagnosed in 12 patients and hence the prevalence of PAH came out to be 8 % (95 % CI: 3.65; 12.34). Significant association of PAH has been observed with viral load (p value = 0.04). While no significant association has been found between PAH and CD4 count. ConclusionPAH in HIV patients was found to be 8% which is considerably higher than the already established global prevalence. Hence, PAH should be an important consideration for clinicians in differential diagnosis of dyspnea in HIV patients.

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.

Abstract 16991: Rare Variants in BMP10 Confer Risk of Pulmonary Arterial Hypertension

Background: Genetic mutations in the genes of BMPR2 pathway are the most crucial cause of pulmonary arterial hypertension. BMP10 is the major ligand of BMPR2, but it remains elusive that whether BMP10 mutation are associated with pulmonary arterial hypertension (PAH). Methods: Whole exome sequencing was applied to screen the BMP10 mutations in 378 patients with congenital heart disease associated with pulmonary arterial hypertension (CHD-PAH). The pathogenicity of variants was assessed by ACMG guideline. Pedigree structures and familial transmission of variants were analyzed for the case who carried the BMP10 mutation. The deleterious function of BMP10 mutations were analyzed via in vitro experiments. Results: Five rare and pathogenic BMP10 variants were identified in five patients with CHD-PAH, including three missense mutations (p.Q74R, p.R96Q, p.I335S) and two nonsense mutations (p.Q116Ter, p.R313Ter). These five cases did not carry mutation in other known PAH risk genes. Five BMP10 mutations were classified as uncertain significance(UVS) or likely pathogenic(LP) variants according to ACMG guideline. It was notworthy that the high impact likely loss-of-function variants in BMP10 were found in 0.53% (2 out of 378) of cases, which was significiantly hihger than those of 0.002% (4 out 251106) in the general population from the GnomAD database (P<10 -4 ). Familial analysis revealed that a case had inherited the heterozygous BMP10 p.I335S missense variant from her affected mother, strongly indicating the co-segregation of BMP10 mutaiton and PAH phenotype. Functional experiments implied that the missense mutation p.I335S and the nonsense mutation p.Q116Ter both resulted in reduced BMP10 protein expression in 293T cells. Conclusion: We identified strong association between rare damaging variants in BMP10 and PAH. The novel BMP10 mutations found in this study will provide new insights into the genetic mechanism of PAH.

Prevalence of pulmonary arterial hypertension in post-tuberculosis lung fibrosis patients: A cross-sectional observational study

Introduction: Post-tuberculosis (TB) lung fibrosis is an infrequently reported cause of Pulmonary arterial hypertension (PAH). Pulmonary TB still being an important global health problem, especially in developing countries, PAH developing after pulmonary TB deserves attention. This study was undertaken to know the prevalence of PAH among patients with post-TB lung fibrosis. Methods: A cross-sectional observational study was carried out in two tertiary care hospitals in Kolkata over a period of 1 year. Sixty adult post-TB lung fibrosis patients without any cardiovascular or other pulmonary comorbidities were included in this study. Results: Out of the 60 patients with varying degrees of lung fibrosis confirmed radiologically, eight patients were found to have PAH (13.33% of the study population). Among the eight cases, six were males and two were females. Five of the males were smokers with a mean of 17.6 pack years of smoking. Out of the eight diagnosed PAH cases, three were mild PAH, four were moderate, and one case had severe PAH (grading based on 2D echocardiography findings). Pulmonary function test (PFT) revealed obstructive pattern in three cases, restrictive pattern in three cases, and mixed in two cases. On PFT, smokers with PAH exhibited obstructive pattern and mixed pattern, whereas the nonsmoker PAH cases exhibited restrictive pattern. Conclusion: All post-TB lung fibrosis cases must be followed up at regular intervals and screened to rule out PAH. Early diagnosis and prompt treatment of the cases will help to reduce morbidity and mortality of the disease which otherwise has a poor prognosis.

Thiamine-responsive acute pulmonary hypertension – A case series and review from a pediatric ICU

Pulmonary hypertension is seen in approximately 10% of infants with respiratory distress admitting to pediatric ICUs. Causes can be idiopathic or secondary to lung parenchymal or vascular diseases. Among various causes of pulmonary arterial hypertension, thiamine deficiency (TD) is one of the reversible causes. TD is still prevalent in selected parts of India. This review outlines five typical patients admitted to KIMS, Amalapuram, with thiamine-responsive acute pulmonary hypertension who responded dramatically to thiamine supplementation. It can cause life-threatening pulmonary hypertension in exclusively breastfeeding infants of mothers who are on a restricted diet predominantly consisting of polished and washed rice which can contribute to infant mortality. Thiamine administration based on clinical suspicion and echo findings leads to remarkable recovery. To tackle this fatal disease, a very high degree of awareness and thiamine supplementation in relevant geographical areas is required.

Relationship Between Soluble ST2 Level and Chronic Thromboembolic Pulmonary Hypertension (CTEPH) in Acute Pulmonary Embolism (PE) Patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease characterized by right heart failure following recurrent pulmonary embolism (PE). It is important to know the predictors of the development of CTEPH after PE as it is a treatable cause of pulmonary arterial hypertension. Soluble ST2 is a biomarker closely associated with heart failure and the inflammatory process. The aim of this study was to investigate the relationship between sST2 level and the development of CTEPH in patients with PE. Baseline characteristics, electrocardiographic findings, laboratory findings, transthoracic echocardiography (TTE) findings, location, and extent of involvement in CT pulmonary angiography were recorded in 100 patients with acute PE included in our prospective study. Treatment modalities and treatment durations were followed. Ventilation-perfusion scintigraphy was performed in patients with a systolic pulmonary artery pressure (sPAP) of 35 mmHg or more on TTE and residual thrombus on CT pulmonary angiography after at least three months of anticoagulant use. In the case of findings compatible with CTEPH in these examinations, patients were diagnosed with CTEPH by right heart catheterization. The sST2 levels obtained from all patients at admission were evaluated between the groups of patients with and without CTEPH. CTEPH was observed in 11 of the 100 patients who participated in the trial, with a median follow-up of 284 ± 60 days. The mean age of the 11 patients with CTEPH was 67 ± 10 years; five were males and six were females. The mean age of 89 patients without CTEPH was 65 ± 18 years, 36 were males and 53 were females. The sST2 values of the group with CTEPH were found to be statistically significantly higher than those of patients without CTEPH [193.7 (184.3-244.7) vs 58.6 (29.5-122.9) p=0.020]. This receiver operating characteristic (ROC) curve shows that the optimal cutoff point of sST2 levels in the prediction of CTEPH was > 157.4with specificity of83.7% and sensitivity of 81.8% (area under the curve = 0.783; 95% CI, 1.005-1.027; p < 0.001). In acute PE patients, sST2 levels may be a useful biomarker to predict the development of CTEPH.

MicroRNA-31 regulates TNF-α and IL-17A co-induced-endothelial cell apoptosis by repressing E2F6

Vascular endothelial cell (VEC) apoptosis is the fundamental cause of pulmonary arterial hypertension. MicroRNA-31 (MiR-31) is a novel target for hypertension treatment. However, the role and mechanism of miR-31 in the apoptosis of VECs remain unclear. The purpose of this study is to determine whether miR-31 plays an important role in VEC apoptosis as well as the detailed mechanisms involved. We found that pro-inflammatory cytokines IL-17A and TNF-α were highly expressed in serum and aorta, and the expression of miR-31 was significantly increased in aortic intimal tissue from Angiotensin II (AngII)- induced hypertensive mice (WT-AngII) compared with control mice (WT-NC). In vitro, co-stimulation of VECs with IL-17A and TNF-α resulted in increased expression of miR-31 and VEC apoptosis. MiR-31 inhibition strikingly decreased TNF-α and IL-17A co-induced VEC apoptosis. Mechanistically, in IL-17A and TNF-α co-stimulated VECs (co-induced VECs), we found that the activation of the NF-κB signal effectively increased the expression of miR-31. Dual-luciferase reporter gene assay revealed that miR-31 directly targeted and inhibited the expression of the E2F transcription factor 6 (E2F6). The expression of E2F6 was decreased in Co-induced VECs. MiR-31 inhibition significantly alleviated the decreased expression of E2F6 in co-induced VECs. Consistent with the co-stimulated effect of IL-17A and TNF-α on VECs, transfection of siRNA E2F6 induced cell apoptosis without the stimulation of the above cytokines. In conclusion, TNF-α and IL-17A generated in the aortic vascular tissue and serum from Ang II-induced hypertensive mice could trigger VECs apoptosis by the miR-31/E2F6 axis. To sum up, our study suggests that the key factor between cytokine co-stimulation effect and VEC apoptosis was miR-31/E2F6 axis, which was mainly regulated by NF-қB signaling pathway. This gives us a new sight to treat hypertension-associated VR.

Pulmonary vascular disease as a complication of pediatric congenital heart diseases.

Congenital and acquired heart diseases can cause pulmonary hypertension (PH) in children, either by increasing pulmonary blood flow (PBF), left atrial pressure (LAp), and/or pulmonary vascular resistance (PVR). Pathophysiological process of pulmonary vascular disease (PVD) in different types of congenital heart diseases (CHDs) are reviewed hereafter. As with other types of PH, a rigorous diagnostic evaluation is mandatory to characterize the etiology of the PH, rule out other or additional causes of PH, and establish a risk profile. Cardiac catheterization remains the gold standard exam for PH diagnosis. Treatment of pulmonary arterial hypertension (PAH) associated with CHD (PAH-CHD) can then be started according to the recent guidelines recommendations, although most of the evidence is extrapolated from studies on other causes of PAH. PH in pediatric heart disease is often multifactorial, and sometimes unclassifiable, making the management of these patients complicated. The operability of patients with a prevalent left-to-right shunt and increase of PVR, the management of children with PH associated with left-sided heart disease, the challenges of pulmonary vascular disorders in children with univentricular heart physiology and the role of vasodilator therapy in failing Fontan patients are some of the hot topics discussed in this review.

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

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

Correlation of Echoradiography Pulmonary to Left Atrial Ratio (ePLAR) with Right Heart Catheterization Parameters in Pulmonal Arterial Hypertension

Abstract Funding Acknowledgements Type of funding sources: None. Background Until now, right heart catheterization is still the gold standard for pulmonary hypertension examination, but this examination is invasive, has a risk of action, and is limited. Echocardiography provides an alternative examination that is easier, safer, cheaper, and more effective in evaluating pulmonary hypertension. Various echocardiographic parameters have been used to assess pulmonary hypertension but no parameter can distinguish the hemodynamics of pulmonary hypertension. Echocardiography pulmonary to left atrial ratio (ePLAR) is a new echocardiographic parameter that is formulated by the maximal tricuspid regurgitation velocity (TR Vmax) divided by the mitral E/e'. This simple parameter can determine precapillary pulmonary hypertension Purpose The aim of this study is to determine the correlation of ePLAR with right heart catheterization parameters in pulmonary arterial hypertension patients. Methods This is a cross-sectional study in the pulmonary arterial hypertension group conducted at M. Djamil Hospital from August 2021 to May 2022. Respondents underwent an echocardiography and right heart catheterization prosedure. The correlation of ePLAR with right heart catheterization parameters was assessed using the Spearman correlation test. Result The research subjects were 32 patients with pulmonary arterial hypertension, 20 women and 12 men, the median age was 21.50 (8-54) years and the most common cause of pulmonary arterial hypertension was congenital heart disease. The median value of ePLAR was 0.44(0.30-0.77) m/s, while the mean value of mPAP was 54.40 ± 16.24 mmHg and the median value of PVR was 8.39 (3.21-29.50) WU. Based on the Spearman correlation test, it was found that the ePLAR had a moderate positive correlation (r=0.554) with the mPAP and was statistically significant (p=0.001). The ePLAR had a strong positive correlation (r=0.779) with the PVR and was statistically significant (p&amp;lt;0.001) Conclusion There was a moderate and significant positive correlation between ePLAR and mPAP, there was a strong and significant positive correlation between ePLAR and PVR in patients with pulmonary arterial hypertension.

BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the BMPR2 gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.

Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension

PurposeThe aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families. MethodsWe performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis. ResultsWe identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH. ConclusionThe calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.

Examining the Effectiveness of Monotherapy versus Combination Therapy for Pulmonary Hypertension in Patients with Congenital Heart Disease: A Short-Term Outcome Comparison Study

Introduction: Pulmonary arterial hypertension (PAH) is a serious condition characterized by a gradual increase in pulmonary vascular resistance, which can lead to right heart failure and death. Although the underlying cause of PAH is complex, there are three main pathways involved in the disease: endothelin, nitric oxide, and prostacyclin. Medications that target these pathways have been effective in extending the lives of PAH patients, but the disease remains fatal. Combining different medications is an attractive option for treating PAH, and this study aimed to compare the outcomes of using a single medication versus combining multiple medications over a short period of time.&#x0D; Aim of the study: The study aimed to compare the short-term outcome of monotherapy and combination therapy in the treatment of Pulmonary hypertension&#x0D; Methods: This randomized control trial study was conducted at the Department of Cardiology, Ranpur Medical College, Rangpur, Bangladesh. The study duration was 2 years, from January 2019 to January 2021. During this period, a total of 140 participants were selected for the study following the inclusion, and exclusion criteria from those diagnosed case of pulmonary hypertension with congenital heart disease admitted to the Pediatric Cardiology Department, Bangabandhu Sheikh Mujib Medical University, NICVD, NHF. The selected participants were then divided into two groups of 70 each through random selection.&#x0D; Result: The majority of the participants in this study were between 12 to 15 years of age, with 54.3% in Group A (treated with Sildenafil) and 60.0% in Group B (treated with a combination of medications). Group A consisted of 70 patients, of whom 28 (40.0%) were male and 42 (60.0%) were female. In Group B, 24 (34.4%) patients were male and 46 (65.7%) were female. There were no significant differences between the two groups in terms of mean age or sex. The most common congenital heart defect among the participants was ventricular septal defects (VSD), followed by atrioventricular septal defects (AVSD), and atrial septal defects (ASD). After 3 and 6 months of follow-up, the study found statistically significant differences between the two groups in terms of SpO2 per exercise, 6-minute walk distance, SpO2 after exercise, and alanine aminotransferase. However, there were no significant differences in adverse effects between the two groups. Pulmonary artery systolic pressure (PASP) was significantly reduced in the combination therapy group compared to the monotherapy group.&#x0D; Conclusion: The study found that combining Bosentan with oral Sildenafil medication is a safe and effective treatment for patients with PAH associated with CHD. The combination therapy resulted in significant improvements in clinical status, effort SpO2, exercise tolerance, hemodynamics, and PASP after 3- and 6-month follow-ups. Therefore, the study concludes that combination therapy is more successful than monotherapy for treating PAH associated with CHD.&#x0D; &#x0D;

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

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

Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment.

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet's disease and adult-onset Still's disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines. Key Points • Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH). • CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs. • While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs. • CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH.

Clinical Management and Outcomes of Patients With Portopulmonary Hypertension Enrolled in the Japanese Multicenter Registry.

Background: Portopulmonary hypertension (PoPH) is one of the major underlying causes of pulmonary arterial hypertension (PAH). However, PoPH, especially treatment strategies, has been poorly studied. Therefore, this study evaluated current treatments for PoPH, their efficacy, and clinical outcomes of patients with PoPH. Methods and Results: Clinical data were collected for patients with PoPH who were enrolled in the Japan Pulmonary Hypertension Registry between 2008 and 2021. Hemodynamic changes, functional class, and clinical outcomes were compared between patients with PoPH treated with monotherapy and those treated with combination therapies. Clinical data were analyzed for 62 patients with PoPH, including 25 treatment-naïve patients, from 21 centers in Japan. In more than half the patients, PAH-specific therapy improved the New York Heart Association functional class by at least one class. The 3- and 5-year survival rates of these patients were 88.5% (95% confidence interval [CI] 76.0-94.7) and 80.2% (95% CI 64.8-89.3), respectively. Forty-one (66.1%) patients received combination therapy. Compared with patients who had received monotherapy, the mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index were significantly improved in patients who had undergone combination therapies. Conclusions: Combination therapy was commonly used in patients with PoPH with a favorable prognosis. Combination therapies resulted in significant hemodynamic improvement without an increased risk of side effects.

Abstract 9727: Reduced Bmpr2 Causes a Decrease in Foxf1 That Links Unrepaired DNA Damage to Persistent Pulmonary Hypertension

Introduction: B MPR2 mutation is the most common genetic cause of pulmonary arterial hypertension (PAH). Loss of BMPR2 causes pulmonary arterial (PA) endothelial cell (EC) dysfunction and impairs EC-mediated suppression of smooth muscle cells proliferation. These are characteristic features of PAH vascular cells as is the presence of DNA damage that can be induced by oxidative stress. We previously showed that EC- Bmpr2 -/- mice have persistent pulmonary hypertension (PH) with reoxygenation after hypoxia. However, the role of DNA damage in causing persistent PH related to loss of BMPR2 and oxidative stress is unknown. Hypothesis: We hypothesize that loss of BMPR2 causes unrepaired DNA damage and persistent PH by altering the expression of genes that maintain EC homeostasis. Methods and Results: DNA damage assessed by γH2AX foci was observed in PAEC of EC- Bmpr2 -/- mice in room air, that was more extensive after reoxygenation (10% hypoxia for 3 weeks followed by recovery in room-air for 4 weeks). Deletion of the DNA damage sensor ataxia-telangiectasia mutated (ATM) in EC of mice (EC- Atm -/- ) also resulted in persistent DNA damage and PH. RNA sequencing of PAEC after reoxygenation in EC- Bmpr2 -/- and EC- Atm -/- mice vs. controls showed downregulated EC differentiation and development genes enriched in biding motifs for Foxf1, a transcription factor associated with DNA repair and angiogenesis. Foxf1 expression was reduced in PAEC with loss of BMPR2 or ATM. Loss of Foxf1 decreased angiogenic genes Cldn5 and Vegfr2 , and DNA damage response genes Atm and p53 , and impaired PAEC migration and tube formation. Foxf1 overexpression increased these genes in PAEC. Immunohistochemistry showed decreased FOXF1 in PAEC of human pulmonary vascular lesions. Delivery of Foxf1 to EC- Bmpr2 -/- mice with an AAV2-peptide targeting the PA endothelium attenuated DNA damage in PAEC, restored angiogenesis genes and completely reversed persistent PH returning right ventricular systolic pressure to normal levels. Conclusions: We link loss of BMPR2 and DNA damage sensing in PAEC to persistent DNA damage and PAH and show that both are mediated by reduced FOXF1 . In EC- Bmpr2 -/- mice, Foxf1 gene therapy attenuated DNA damage restored angiogenesis genes, and prevented persistent PH.