Idiopathic Pulmonary Arterial Hypertension Research Articles

Predicting Peri-Operative Cardiorespiratory Adverse Events in Children with Idiopathic Pulmonary Arterial Hypertension Undergoing Cardiac Catheterization Using Echocardiography: A Cohort Study.

General anesthesia in children with idiopathic pulmonary arterial hypertension (PAH) carries an increased risk of peri-operative cardiorespiratory complications though risk stratifying individual children pre-operatively remains difficult. We report the incidence and echocardiographic risk factors for adverse events in children with PAH undergoing general anesthesia for cardiac catheterization. Echocardiographic, hemodynamic, and adverse event data from consecutive PAH patients are reported. A multivariable predictive model was developed from echocardiographic variables identified by Bayesian univariable logistic regression. Model performance was reported by area under the curve for receiver operating characteristics (AUCroc) and precision/recall (AUCpr) and a pre-operative scoring system derived (0-100). Ninety-three children underwent 158 cardiac catheterizations with mean age 8.8 ± 4.6years. Adverse events (n = 42) occurred in 15 patients (16%) during 16 catheterizations (10%) including cardiopulmonary resuscitation (n = 5, 3%), electrocardiographic changes (n = 3, 2%), significant hypotension (n = 2, 1%), stridor (n = 1, 1%), and death (n = 2, 1%). A multivariable model (age, right ventricular dysfunction, and dilatation, pulmonary and tricuspid regurgitation severity, and maximal velocity) was highly predictive of adverse events (AUCroc 0.86, 95% CI 0.75 to 1.00; AUCpr 0.68, 95% CI 0.50 to 0.91; baseline AUCpr 0.10). Pre-operative risk scores were higher in those who had a subsequent adverse event (median 47, IQR 43 to 53) than in those who did not (median 23, IQR 15 to 33). Pre-operative echocardiography informs the risk of peri-operative adverse events and may therefore be useful both for consent and multi-disciplinary care planning.

Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism.

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.

The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

Analysis of genes characterizing chronic thrombosis and associated pathways in chronic thromboembolic pulmonary hypertension.

In chronic thromboembolic pulmonary hypertension (CTEPH), fibrosis of thrombi in the lumen of blood vessels and obstruction of blood vessels are important factors in the progression of the disease. Therefore, it is important to explore the key genes that lead to chronic thrombosis in order to understand the development of CTEPH, and at the same time, it is beneficial to provide new directions for early identification, disease prevention, clinical diagnosis and treatment, and development of novel therapeutic agents. The GSE130391 dataset was downloaded from the Gene Expression Omnibus (GEO) public database, which includes the full gene expression profiles of patients with CTEPH and Idiopathic Pulmonary Arterial Hypertension (IPAH). Differentially Expressed Genes (DEGs) of CTEPH and IPAH were screened, and then Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) functional enrichment analyses were performed on the DEGs; Weighted Gene Co-Expression Network Analysis (WGCNA) to screen the key gene modules and take the intersection genes of DEGs and the key module genes in WGCNA; STRING database was used to construct the protein-protein interaction (PPI) network; and cytoHubba analysis was performed to identify the hub genes. A total of 924 DEGs were screened, and the MEturquoise module with the strongest correlation was selected to take the intersection with DEGs A total of 757 intersecting genes were screened. The top ten hub genes were analyzed by cytoHubba: IL-1B, CXCL8, CCL22, CCL5, CCL20, TNF, IL-12B, JUN, EP300, and CCL4. IL-1B, CXCL8, CCL22, CCL5, CCL20, TNF, IL-12B, JUN, EP300, and CCL4 have diagnostic and therapeutic value in CTEPH disease, especially playing a role in chronic thrombosis. The discovery of NF-κB, AP-1 transcription factors, and TNF signaling pathway through pivotal genes may be involved in the disease progression process.

Pulmonary Effects of Traumatic Brain Injury in Mice: A Gene Set Enrichment Analysis.

Acute lung injury occurs in 20-25% of cases following traumatic brain injury (TBI). We investigated changes in lung transcriptome expression post-TBI using animal models and bioinformatics. Employing unilateral controlled cortical impact for TBI, we conducted microarray analysis after lung acquisition, followed by gene set enrichment analysis of differentially expressed genes. Our findings indicate significant upregulation of inflammation-related genes and downregulation of nervous system genes. There was enhanced infiltration of adaptive immune cells, evidenced by positive enrichment in Lung-Th1, CD4, and CD8 T cells. Analysis using the Tabula Sapiens database revealed enrichment in lung-adventitial cells, pericytes, myofibroblasts, and fibroblasts, indicating potential effects on lung vasculature and fibrosis. Gene set enrichment analysis linked TBI to lung diseases, notably idiopathic pulmonary hypertension. A Venn diagram overlap analysis identified a common set of 20 genes, with FOSL2 showing the most significant fold change. Additionally, we observed a significant increase in ADRA1A→IL6 production post-TBI using the L1000 library. Our study highlights the impact of brain trauma on lung injury, revealing crucial gene expression changes related to immune cell infiltration, cytokine production, and potential alterations in lung vasculature and fibrosis, along with a specific spectrum of disease influence.

Tumor biomarkers in evaluating the severity and prognosis of idiopathic pulmonary arterial hypertension: Acomprehensive analysis.

Inflammation contributes to development of idiopathic pulmonary arterial hypertension (IPAH), and tumor biomarkers can reflect inflammatory and immune status. We aimed to determine the value of tumor biomarkers in IPAH comprehensively. We enrolled 315 patients with IPAH retrospectively. Tumor biomarkers were correlated with established indicators of pulmonary hypertension severity. Multivariable Cox regression found that AFP (hazard ratio [HR]: 1.587, 95% confidence interval [CI]: 1.014-2.482, p = 0.043) and CA125 (HR: 2.018, 95% CI: 1.163-3.504, p = 0.013) could independently predict prognosis of IPAH. The changes of AFP over time were associated with prognosis of patients, each 1 ng/mL increase in AFP was associated with 5.4% increased risk of clinical worsening (HR: 1.054, 95% CI: 1.001-1.110, p = 0.046), enabling detection of disease progression. Moreover, beyond well-validated PH biomarkers, CA125 was still of prognostic value in the low-risk patients (HR: 1.014, 95% CI: 1.004-1.024, p = 0.004), allowing for more accurate risk stratification and prediction of disease outcomes. AFP and CA125 can serve for prognosis prediction, risk stratification, and dynamic monitor in patients with IPAH.

Clinical Correlates of a Nonplexiform Vasculopathy in Patients With a Diagnosis of Idiopathic Pulmonary Arterial Hypertension

The clinical phenotype of idiopathic pulmonary arterial hypertension (IPAH) patients has changed. . Whether or not subgroups of IPAH patients have different vascular phenotypes is a subject of debate. What are the histological patterns and their clinical correlates in patients diagnosed with IPAH or hereditary PAH? In this this cross-sectional registry study lung histology of 50 IPAH patients was qualitatively assessed by two experienced pathologists. In addition, quantitative analysis by means of histopathological morphometry using immunohistochemistry was performed. Histopathological characteristics were correlated with clinical and hemodynamic parameters. In this cohort of 50 IPAH patients, a plexiform vasculopathy was observed in 26/50 (52%) of patients, while 24/50 (48%) patients had a non-plexiform vasculopathy. The non-plexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. While hemodynamic parameters were comparable in plexiform versus non-plexiform vasculopathy, patients with non-plexiform vasculopathy were older, more often male, had a stronger history of cigarette smoking and lower diffusing capacity for carbon monoxide (DLCO) at diagnosis No mutations in established PAH genes were found in the non-plexiform group. This study reveals different vascular phenotypes within the current spectrum of patients diagnosed with IPAH, separated by clinical characteristics (age, sex, , history of cigarette smoking, and DLCO at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and non-plexiform / microvascular disease should be taken into account in future research strategies unravelling the pathophysiology of pulmonary hypertension and developing biology-targeted treatment approaches.

Pulmonary arterial hypertension treatment: an individual participant data network meta-analysis.

Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {β: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [β: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [β: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled β: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous β: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.

Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related genetic variants using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, and candidate variants were further validated by polymerase chain reaction and Sanger sequencing in the PAH cohort. In a total of 69 patients, the highest incidence of variants was found in the BMPR2, ATP13A3, and GDF2 genes. Regarding the BMPR2 gene variants, there were two nonsense variants (c.994C>T, p. Arg332*; c.1750C>T, p. Arg584*), one missense variant (c.1478C>T, p. Thr493Ile), and one novel in-frame deletion variant (c.877_888del, p. Leu293_Ser296del). Regarding the GDF2 variants, there was one likely pathogenic nonsense variant (c.259C>T, p. Gln87*) and two missense variants (c.1207G>A, p. Val403Ile; c.38T>C, p. Leu13Pro). The BMPR2 and GDF2 variant subgroups had worse hemodynamics. Moreover, the GDF2 variant patients were younger and had a significantly lower GDF2 value (135.6 ± 36.2 pg/mL, p = 0.002) in comparison to the value in the non-BMPR2/non-GDF2 mutant group (267.8 ± 185.8 pg/mL). The BMPR2 variant carriers had worse hemodynamics compared to the patients with the non-BMPR2/non-GDF2 mutant group. Moreover, there was a significantly lower GDF2 value in the GDF2 variant carriers compared to the control group. GDF2 may be a protective or corrected modifier in certain genetic backgrounds.

Right heart failure as a cause of pulmonary congestion in pulmonary arterial hypertension.

Recent studies have shown that lung ultrasound-assessed pulmonary congestion is worse in heart failure when pulmonary vascular resistance (PVR) is increased, suggesting a paradoxical relationship between right heart failure and increased lung water content. Accordingly, we wondered if lung ultrasound would reveal otherwise clinically silent pulmonary congestion in patients with pulmonary arterial hypertension (PAH). All patients referred for suspicion of PAH in a tertiary centre from January 2020 to December 2022 underwent a complete diagnostic work-up including echocardiography, lung ultrasound and right heart catheterization. Pulmonary congestion was identified by lung ultrasound B-lines using an 8-site scan. The study enrolled 102 patients with idiopathic PAH (mean age 53 ± 13 years; 71% female). World Health Organization functional classes I, II, and III were found in 2%, 52%, and 46% of them, respectively. N-terminal pro-brain natriuretic peptide (NT-proBNP) was 377 pg/ml (interquartile range [IQR] 218-906). B-lines were identified in 77 out of 102 patients (75%), with a median of 3 [IQR 1-5]. At univariable analysis, B-lines were positively correlated with male sex, age, NT-proBNP, systolic pulmonary artery pressure (sPAP), right atrial pressure (RAP), PVR, left ventricular end-diastolic volume and tricuspid annular plane systolic excursion (TAPSE), and negatively with cardiac output and stroke volume. At multivariable analysis, RAP (p < 0.001), TAPSE/sPAP (p = 0.001), and NT-proBNP (p = 0.04) were independent predictors of B-lines. Lung ultrasound commonly discloses pulmonary congestion in PAH. This finding is related to right ventricular to pulmonary artery uncoupling, and may tentatively be explained by increased central venous pressure impeding lymphatic outflow.

Elderly Patients with Idiopathic Pulmonary Hypertension: Clinical Characteristics, Survival, and Risk Stratification in a Single-Center Prospective Registry.

The predictive value of the risk stratification scales in elderly patients with IPAH might differ from that in younger patients. It is unknown whether young and older IPAH patients have the same survival dependence on PAH-specific therapy numbers. The aim of this study was to evaluate the prognostic relevance of risk stratification scales and PAH medication numbers in elderly IPAH patients in comparison with young IPAH patients. A total of 119 patients from a prospective single-center PAH registry were divided into group I < 60 years old (n = 89) and group II ≥ 60 years old (n = 30). ESC/ERS, REVEAL, and REVEAL 2.0 risk stratification scores were assessed at baseline, as well as H2FpEF score and survival at follow-up. During a mean follow-up period of 2.9 years (1.63; 6.0), 42 (35.3%) patients died; at 1, 2, 3, 5, 7, and 10 years, survival was 95%, 88.6%, 78.5%, 61.7%, 48.5%, and 33.7%, respectively. No survival differences were observed between the two groups, despite the use of monotherapy in the elderly patients. The best predictive REVEAL value in elderly patients (IPAH patients ≥ 60 years) was AUC 0.73 (0.56-0.91), p = 0.03; and in patients with LHD comorbidities in the entire cohort, it was AUC 0.73 (0.59-0.87), p < 0.009. Factors independently associated with death in the entire cohort were CKD (p = 0.01, HR 0.2), the right-to-left ventricle dimension ratio (p = 0.0047, HR 5.97), and NT-proBNP > 1400 pg/mL (p = 0.008, HR 3.18). Risk stratification in the elderly IPAH patients requires a fundamentally different approach than that of younger patients, taking into account the initial limitations in physical performance and comorbidities that interfere with current assessment scores. The REVEAL score reliably stratifies patients at any age and LHD comorbidities. The initial monotherapy seems to be reasonable in patients over 60 years. Selection tools for initial combination PAH therapy in older IPAH patients with comorbidities need to be validated in prospective observational studies.

Up-regulated expression of two-pore domain K+ channels, KCNK1 and KCNK2, is involved in the proliferation and migration of pulmonary arterial smooth muscle cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe and rare disease in the cardiopulmonary system. Its pathogenesis involves vascular remodeling of the pulmonary artery, which results in progressive increases in pulmonary arterial pressure. Chronically increased pulmonary arterial pressure causes right ventricular hypertrophy and subsequent right heart failure. Pulmonary vascular remodeling is attributed to the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are induced by enhanced Ca2+ signaling following the up-/down-regulation of ion channel expression. In the present study, the functional expression of two-pore domain potassium KCNK channels was investigated in PASMCs from idiopathic PAH (IPAH) patients and experimental pulmonary hypertensive (PH) animals. In IPAH-PASMCs, the expression of KCNK1/TWIK1 and KCNK2/TREK1 channels was up-regulated, whereas that of KCNK3/TASK1 and KCNK6/TWIK2 channels was down-regulated. The similar up-regulated expression of KCNK1 and KCNK2 channels was observed in the pulmonary arterial smooth muscles of monocrotaline-induced PH rats, Sugen 5416/hypoxia-induced PH rats, and hypoxia-induced PH mice. The facilitated proliferation of IPAH-PASMCs was suppressed by the KCNK channel blockers, quinine and tetrapentylammonium. The migration of IPAH-PASMCs was also suppressed by these channel blockers. Furthermore, increases in the proliferation and migration were inhibited by the siRNA knockdown of KCNK1 or KCNK2 channels. The siRNA knockdown also caused membrane depolarization and subsequent decrease in cytosolic [Ca2+]. The phosphorylated level of c-Jun N-terminal kinase (JNK) was elevated in IPAH-PASMCs compared to normal-PASMCs. The increased phosphorylation was significantly reduced by the siRNA knockdown of KCNK1 or KCNK2 channels. Collectively, these findings indicate that the up-regulated expression of KCNK1 and KCNK2 channels facilitates the proliferation and migration of PASMCs via enhanced Ca2+ signaling and JNK signaling pathway, which is associated with vascular remodeling in PAH.

Application of a modified clinical classification for pulmonary arterial hypertension associated with congenital heart disease in children: emphasis on atrial septal defects and transposition of the great arteries. An analysis from the TOPP registry.

A proportion of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) do not fit in the current classification. We aimed to analyse the applicability of an adapted clinical classification of PAH-CHD to pediatric patients using the TOPP-1 registry (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) and focus on atrial septal defects (ASD) and transposition of the great arteries (TGA). Hemodynamic and clinical data of all patients with PAH-CHD in the TOPP cohort were reviewed. Patients were classified according to predefined ABCDE categories (A: Eisenmenger syndrome, B: left-to-right shunt, C: coincidental defects, including all ASDs, D: corrected CHD, E: TGA), or as complex CHD (group 5), by 2 independent investigators. In case of disagreement, a third reviewer could either settle a final decision, or the patient was deemed not classifiable. Survival curves were calculated for each group and compared to idiopathic PAH patients of the registry. A total of 223 out of 531 patients in the registry had PAH-CHD, and 193 were categorized to the following groups: A 39(20%), B 27(14%), C 62(32%) including 43 ASDs, D 58(30%), E 7(4%), whereas 6 patients were categorized as group 5, and 10 patients were unable to be classified. No survival difference could be demonstrated between the groups. This modified classification seems to be more applicable to pediatric PAH-CHD patients than the previous classification, but some patients with PAH-CHD who never had a shunt remain unclassifiable. The role of ASD in pediatric PH should be reconsidered.

Lung Transplantation in Pulmonary Arterial Hypertension: The Portuguese Experience

In patients with pulmonary arterial hypertension (PAH), refractory to medical therapy, lung transplantation emerges as an option. This study describes the outcomes of 8 PAH patients who underwent lung transplantation. A retrospective, single-center study was conducted among patients with PAH who underwent lung transplantation in our center. Patients had a median age of 46 years, with female sex predominance (75%). Causes of HAP were pulmonary veno-occlusive disease (n = 5, 62.5%), idiopathic PAH (n = 2, 25%), and heritable PAH (n = 1, 12.5%). Pre-transplant hemodynamics revealed a median mean pulmonary artery pressure of 58.5 mm Hg (48-86). All patients received bilateral lung transplants with extracorporeal membrane oxygenation support, displaying immediate post-transplant hemodynamic improvement. Primary graft dysfunction grade 3 (PGD 3) was observed in 75% of patients. Five patients (62.5%) died, with a 72.9% survival at 12 months and 29.2% at 24 months post-transplantation. Our study reveals the complexity and challenges of lung transplants in patients with PAH. Despite notable immediate hemodynamic improvements, high rates of PGD 3 and the survival rate remain a concern. Further research to define optimal peri and post-transplant management to improve survival is required.

Idiopathic Pulmonary Hypertension and in Situ Thromboembolism: A Difficult Case in Clinical Practice

Pulmonary hypertension is a complex syndrome for differential diagnosis, which is the outcome of various pathological conditions. With the exclusion of the two most common causes of pulmonary hypertension, such as pathology of the left heart chambers and pulmonary embolism, further search for etiology often becomes problematic. Despite the emergence of a number of international and domestic recommendations, as well as certain successes in drug therapy, the long-term prognosis in patients with pulmonary arterial hypertension remains unfavorable. In the description of this clinical case in a 39-year-old woman suffering from idiopathic pulmonary arterial hypertension, the main complaint of the patient was very non-specific. The woman could not bear the child, all her attempts, lasting more than 19 years, remained unsuccessful. Even in absolutely healthy women, pregnancy is associated with the highest risks and is a powerful “test” of the body, not to mention patients suffering from rare diseases. The patient has a “subacute” course and a fairly rapid progression of the disease with a significant deterioration in the quality of life, which led to the impossibility of carrying a pregnancy. There were also signs that aggravated the prognosis, such as increased dyspnea, loss of consciousness, a significant decrease in working capacity and a high degree of pulmonary hypertension (according to echocardiography, systolic pressure in the pulmonary artery &gt; 128 mm Hg). Due to the ineffectiveness of standard therapy with a selective inhibitor of cycloguanosine monophosphate — specific phosphodiesterase type 5 — sildenafil; the option of specific therapy for pulmonary hypertension was considered, which made it possible to change the situation and bring the patient into a stable state and draw conclusions about the pregnancy.

Implantation of atrial flow regulator devices in patients with congenital heart disease and children with severe pulmonary hypertension or cardiomyopathy-an international multicenter case series.

The Occlutech Atrial Flow Regulator (AFR) is a self-expandable double-disc nitinol device with a central fenestration. Its use has been approved in the adult population with heart failure and described for pulmonary hypertension (PH). Only case reports and small series have been published about its use in the paediatric population and for congenital heart disease (CHD). The authors sought to investigate the feasibility, safety, and short-term follow-up of AFR implantation in patients with CHD or children with PH or cardiomyopathy. This is a multicenter retrospective study involving 10 centers worldwide. Patients of any age with CHD or patients aged < 18 years with PH or cardiomyopathy needing AFR implantation were included. A total of 40 patients underwent AFR implantation. The median age of the population at the time of the procedure was 58.5 months (IQR: 31.5-142.5) and the median weight was 17 kg (IQR: 10-46). A total of 26 (65.0%) patients had CHD, nine (22.5%) children, a cardiomyopathy, and five (12.5%), a structurally normal heart. The implantation success rate was 100%. There were two early and one late device thrombosis. Two patients (5.0%) with dilated cardiomyopathy on extracorporeal membrane oxygenator (ECMO) died during the hospital stay. At a median follow-up of 330 days (IQR: 125-593), 37 (92.5%) patients were alive. At follow-up, 20 patients improved their New York Heart Association (NYHA) class, 12 patients did not change their NYHA class, and one patient with idiopathic PH worsened. AFR implantation in patients with CHD and children with severe PH or cardiomyopathy is promising and seems to have beneficial effects at short-term follow-up.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Impulse oscillometry in patients with pulmonary arterial hypertension: an exploratory study

IntroductionStudies suggest peripheral airway abnormalities in Pulmonary Arterial Hypertension (PAH). Impulse Oscillometry (IOS) is a noninvasive and sensitive technique for assessing the small airways. It evaluates the impedance of the respiratory system ‒ Resistance (R) and reactance (X) ‒ to a pulse of sound waves sent to the lungs, in a range of frequencies (5‒20 Hz). MethodResistance variables: R5, R20, R5-R20 and reactance variables: AX (reactance area) and Fres (resonance frequency). The aim is to evaluate R and X in patients with idiopathic PAH (IPAH) and to investigate whether there is a correlation between IOS and spirometry. ResultsThirteen IPAH patients and 11 healthy subjects matched for sex and age underwent IOS and spirometry. IPAH patients had lower FVC and FEV1 values (p < 0.001), VEF1/CVF (p = 0.049) and FEF 25-75 (p = 0.006) than healthy patients. At IOS, IPAH patients showed lower tidal volumes and higher AX (p < 0.05) compared to healthy individuals, and 53.8 of patients had R5-R20 values ≥ 0.07 kPa/L/s. Correlation analysis: X5, AX, R5-R20 and Fres showed moderate correlation with FVC (p = 0.036 r = 0.585, p = 0.001 r = -0.687, p = 0.005 r = -0.726 and p = 0.027 r = -0.610); Fres (p = 0.012 r = -0.669) and AX (p = 0.006 r = -0.711) correlated with FEV1; [R5 and R20, (R5-R20)] also correlated with FEV1 (p < 0.001 r = -0.573, p = 0.020 r = -0.634 and p = 0.010 r = -0.683, respectively) in the IPAH group. There were also moderate correlations of FEF 25–75 % with Z5 (p = 0.041), R5 (p = 0.018), Fres (p = 0.043) and AX (p = 0.023). DiscussionPatients showed changes suggestive of increased resistance and reactance in the IOS compared to healthy individuals, and the IOS findings showed a good correlation with spirometry variables.

Role of the Systemic Inflammatory Response Index in Predicting Disease Severity and Prognosis in Idiopathic Pulmonary Arterial Hypertension.

Mounting evidence indicates a possible connection between the systemic inflammatory response index (SIRI) and the prognosis of heart failure, but its role in idiopathic pulmonary arterial hypertension (IPAH) is not well understood. This study aimed to investigate the relationship between SIRI and variables such as functional ability, echocardiography results, hemodynamic measurements, and long-term outcomes in patients with IPAH. The study included 426 consecutive IPAH patients who underwent right heart catheterization at Fuwai Hospital from January 2013 to December 2020. SIRI was calculated using composite inflammation indicators from routine blood tests. The main outcome measure was clinical deterioration. Spearman correlation coefficients were used to assess associations between SIRI and indicators of IPAH severity. Receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal SIRI threshold and predictive ability. Kaplan-Meier analysis and Cox proportional hazard models were used to examine the relationship between SIRI and clinical deterioration. SIRI showed positive associations with indicators such as N-terminal pro-brain natriuretic peptide, right ventricular end-diastolic diameter, pericardial effusion, mean pulmonary arterial pressure, and pulmonary vascular resistance. Conversely, SIRI had inverse relationships with 6-minute walking distance and left ventricular end-diastolic diameter. Kaplan-Meier curves revealed a significantly higher rate of clinical deterioration in individuals with SIRI > 0.741 compared to those with SIRI ≤ 0.741 (P < 0.001). Adjusted Cox analysis showed SIRI remained an independent predictor of clinical worsening (hazard ratio 1.366, 95% confidence interval 1.073-1.738, P = 0.011). ROC analysis demonstrated SIRI provided additional predictive value beyond the risk assessment score of the European Society of Cardiology/European Respiratory Society. In summary, SIRI could predict the severity and prognosis of IPAH independently. It was associated with various indicators of IPAH severity and was a significant predictor of clinical deterioration. SIRI also offered additional predictive value beyond existing risk assessment scores.

The diagnostic journey of pulmonary arterial hypertension patients: results from a multinational real-world survey.

Pulmonary arterial hypertension (PAH) is a life-threatening, progressive disease often diagnosed late in its course. To present patient-reported data that were captured within a large, multinational, point-in-time survey of PAH-treating physicians and their patients to better understand the diagnostic journey. Cross-sectional survey conducted in five European countries (EU5), Japan and the USA. PAH-treating pulmonologists, cardiologists, rheumatologists or internists (USA only) completed a patient record form (PRF) for the next four consecutive adult PAH patients they saw; these patients filled in a patient self-completion (PSC) form on an anonymous, voluntary basis. Our report focuses on patient data; data are from PSC forms unless stated otherwise. Physician-reported PRFs and self-completed PSC forms were obtained for 1152 and 572 patients, respectively. Patients' mean (SD) age was 59.1 (14.0) years, 55.6% were female, and 57.3% had idiopathic PAH. Patient-reported data showed an average delay of 17.0 months between symptom onset and PAH diagnosis. This is longer than physicians estimated (13.8 months): this disparity may be partly due to the time taken by patients to consult a physician about their symptoms [9.6 months overall, longest in the USA (15.3 months)]. Most patients (71.6%) initially consulted primary care physicians about their symptoms and 76.4% of patients were referred to a specialist. Misdiagnoses occurred in 40.9% of patients [most frequent in the USA (51.3%), least common in Japan (27.6%)] and they saw an average of 2.9 physicians overall (3.5 in EU5 versus 2.0 in Japan/USA) before being diagnosed. Diagnosis was most often made by cardiologists (50.4%) or pulmonologists (49.3%). Our data suggest that diagnostic delay in PAH results from patient- and physician-related factors, which differ across regions and include lack of awareness of PAH on both sides. Development of better screening strategies may help address this barrier to timely PAH diagnosis.