Pulmonary Vasculopathy Research Articles

Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in the COPDGene Study.

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

Transpulmonary proteome gradients identify inflammatory pathways involved in the development of pulmonary vasculopathy in heart failure

Abstract Background Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify not only markers but also mediators of PVD by identifying proteins that may be consumed or elaborated across the lungs. Purpose Examine hemodynamics and transpulmonary proteome gradients in HFrEF and controls. Methods 21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged position (02sat &amp;gt; 90%, indicating pulmonary venous blood) and the un-wedged position to obtain transpulmonary proteome gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). Pulmonary artery concentrations ("markers") or transpulmonary fold-change gradients (i.e. putative "mediators") of normalized protein expression (NPX) were plotted against significance; Benjamini–Hochberg FDR&amp;lt;0.05 considered as significant. Results Patients displayed typical characteristics of HFrEF (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%), Controls had similar anthropometrics, gender and age. Comparing all HF to Con, 38 markers of HF were identified (NPX fold-change&amp;gt;2), including 33 up (top 5: NTproBNP, BNP, GDF15, FGF23, IL8) and 5 down. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Comparison of Q1 and Q4 identified 3 protein markers of high PVR in PA blood from HF: chemokine CCL3, TNFRSF13B and surfactant protein-D (PSP-D). Examination of protein gradients from HF lungs (Figure) showed significant uptake of 14 protein mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). In contrast, protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), lymphatic chemokine CCL19, BNP, MMP9, and had more significant transpulmonary release of IL6 and IL33. Across all patients, OSM lung uptake was the strongest correlate of transpulmonary pressure gradient (r=-0.3, p&amp;lt;0.001). Conclusions Lungs of patients with HF, and particularly those with high PVR, display abnormal uptake and release of proinflammatory CC and CXC chemokines and cytokines from IL1 and IL6 family, along with increased pulmonary uptake of IL6-type cytokine Oncostatin-M, a known mediator of lung inflammation and fibrosis, that acts via gp130/JAK/STAT, suggesting a novel role in PVD due to HF.Transpulmonary proteome in HF patients

In vivo study of pulmonary artery remodeling and pulsatility in long Fontan patient

Abstract Background Pulmonary vasculopathy associated with Fontan circulation is a relatively unexplored entity that could have clinical and therapeutic implications. Purpose Our aim was to evaluate the physiology of the pulmonary artery in patients with Fontan circulation using conventional right heart catheterization (RHC) and intravascular ultrasound (IVUS). Methods From December 2022 to January 2024, data from all consecutive Fontan patients undergoing RHC were prospectively collected at a tertiary referral center for adult congenital heart disease. Pressures and pulmonary artery wall high-definition IVUS recordings (OptiCrossTM, 60 MHz, Boston Scientific) were recorded at rest and during apnea. Pathological Fontan pressure was defined when as exceeding 15 mmHg. IVUS pulsatility index was defined as [(systolic lumen area - diastolic lumen area)/(diastolic lumen area) ×100], Peterson's elastic modulus as (pulmonary pulse pressure/IVUS pulsatility index), and area of wall thickness as [(wall area - lumen area)/(lumen area) x100)]. In the literature, the mean ± standard deviation (SD) normal values of elastic modulus and wall thickness area have been reported as 21 ± 1.7 mmHg and 1.4 ± 1.3%, respectively, in healthy patients without pulmonary hypertension (1: doi: 10.1186/s12931-017-0568-z). We define an alteration in intrinsic pulmonary arterial wall viscoelastic properties as an elastic modulus &amp;gt; 70 mmHg, and we define structural pulmonary wall remodeling as an increase in wall thickness area greater than 5%. Results 13 patients were studied. Median age was 28.1 years interquartile range (IQR) (25.6- 41.4), 7 (53.9%) were female, and 4 (30,8%) were in functional New York Heart Associtation (NYHA) class I. RHC and pulmonary arterial wall IVUS values are presented in Figure 1. 6 (46.2%) had Fontan abnormal pressures at rest. All patients showed minimal pulse pressure in the pulmonary arteries synchronized with heart rate, median pulmonary pulse pressure (IQR) 3 (2-4) mmHg. This pulsatility was detected in the IVUS study in all patients, pulsatility index (median (IQR) 4.8 (3.3-10.1)) and elastic modulus (median (IQR) 51.5 (20.5-101.6) mmHg). All of them had some degree of structural pulmonary wall remodeling (&amp;gt;5% wall thickness area), and 10 (76.9%) of them had marked remodeling (&amp;gt; 10%). The median (IQR) of wall thickness area was 13.6 (10.5-18.3) % (Figure 2). We think that the pseudo-normality of the elastic modulus is due to a low pulmonary pulse pressure, however, structural remodeling could be secondary to the endothelial dysfunction present and described in arteries with very low pulsatility. Conclusions The IVUS evaluation of the pulmonary artery in Fontan patients may be useful for revealing significant information regarding pulmonary physiology. Pulmonary wall thickening has been observed, providing insight into altered structural remodeling of the pulmonary arteries in this population.

Monocrotaline - induced pulmonary arterial hypertension: the benefic effects of magnesium sulfate, Rosuvastatin and Sildenafil

Background. Pulmonary arterial hypertension (PAH) is characterized by several maladaptive mechanisms: endothelial dysfunction, oxidative stress, inflammation, pathological remodeling of the pulmonary arterioles, and cellular hypoxia. These mechanisms all favor progressive pulmonary vasculopathy and progressive right ventricle (RV) dysfunction. Aim. This study aims to characterize the experimental model of monocrotaline-induced PAH in rats. Subsequently, by administering Sildenafil, Rosuvastatin, and Magnesium sulfate, we assessed the animals via ultrasonography and assayed biochemical parameters to evaluate the efficacy of the treatment. Methods. 42 male Wistar rats were randomly allocated into six equal groups (n=7) and received a single subcutaneous MCT injection (60 mg/kg dose). Drug therapy with Sildenafil, Rosuvastatin, and Magnesium sulfate in different combinations was initiated 14 days after MCT injection. Fulton Index, RV anterior wall thickness, RV internal diameter, and pulmonary arterial acceleration time/ejection time (PAAT/ PAET) were measured. The following biochemical parameters were also measured: endothelin 1(ET1), brain natriuretic peptide (BNP), nitric oxide (NO) metabolites, vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS). Results. MCT-PAH was a successful experimental model that has fulfilled anatomical, pressure, and biochemical characteristics supporting this fact. Sildenafil monotherapy does not provide any substantial benefit in reducing MCT-PAH. The additive effects of Rosuvastatin + Sildenafil or Sildenafil + Magnesium sulfate significantly reduced the degree of RV hypertrophy and improved RV systolic pressures. However, there were also modest decreases in biochemical parameters compared to Sildenafil alone. The triple drug combination Sildenafil + Rosuvastatin + Magnesium sulfate shows significant results (p&lt;0,001) compared to the previously described drug combinations. The lowest biochemical parameters were recorded: RV anterior wall thickness, RV internal diameter values, and a significant PAAT/PAET ratio improvement. Thanks to their benefits on vascular pathological remodeling, triple drug combinations implicitly reduce ET1, VEGF, NO metabolites, and iNOS values with statistical significance. Conclusions. The beneficial pleiotropic effects of Rosuvastatin combined with Magnesium sulfate (thanks to its potent vasodilator and antioxidant effects) demonstrated its efficacy in this study by improving RV systolic pressures, RV hypertrophy, oxidative stress, and myocardial dysfunction biomarkers.

Phenotypes in pulmonary hypertension.

The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH), the current approach to patient phenotyping integrates clinical, haemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iterations of the PH clinical classification are likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools and clinical trial design, and improve treatment selection in clinical practice.

Chronic Thromboembolic Pulmonary Hypertension

: While the majority of patients have complete resolution of their acute pulmonary embolism (PE) after an adequate course of anticoagulation, some patients remain symptomatic with evidence of chronic PE. Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Chronic Thromboembolic Pulmonary Disease (CTEPD) are terms that describe symptomatic patients with chronic thromboembolic occlusions of the pulmonary arteries with or without pulmonary hypertension, respectively. Here, we review the definitions, epidemiology, pathobiology, diagnosis and management of CTEPH. The chronic PE in CTEPH is essentially a scar in the pulmonary vasculature and is accompanied by a pulmonary arteriolar vasculopathy. Ventilation-perfusion scanning is the most sensitive screening test for CTEPH, and diagnosis must be confirmed by right heart catheterization (RHC). Treatment decisions require a multidisciplinary team and guidance from additional imaging, usually CT or pulmonary angiography. While pulmonary endarterectomy (PEA) to remove the chronic PE surgically is still the first-line treatment for appropriate candidates, there is an expanding role for balloon pulmonary angioplasty (BPA) and medical treatment, as well as multimodality treatment approaches that incorporate all of those options. New imaging modalities and treatment strategies hold the promise to improve our care and management of CTEPH patients in the future.

Myo-inositol trispyrophosphate prevents right ventricular failure and improves survival in monocrotaline-induced pulmonary hypertension in the rat.

Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, and eventually to RV failure. Hypoxia can trigger both pulmonary vasculopathy and RV failure. Therefore, we tested if myo-inositol trispyrophosphate (ITPP), which facilitates oxygen dissociation from haemoglobin, can relieve pulmonary vasculopathy and RV hypoxia, and eventually prevent RV failure and mortality in the rat model of monocrotaline-induced PH. Rats were injected with monocrotaline (PH) or saline (control) and received ITPP or placebo for 5 weeks. Serial echocardiograms were obtained to monitor the disease, pressure-volume loops were recorded and evaluated, myocardial pO2 was measured using a fluorescent probe, and histological and molecular analyses were conducted at the conclusion of the experiment. ITPP reduced PH-related mortality. It had no effect on progressive increase in pulmonary vascular resistance, yet significantly relieved intramyocardial RV hypoxia, which was associated with improvement of RV function and reduction of RV wall stress. ITPP also tended to prevent increased hypoxia inducible factor-1α expression in RV cardiac myocytes but did not affect RV capillary density. Our study suggests that strategies aimed at increasing oxygen delivery to hypoxic RV in PH could potentially be used as adjuncts to other therapies that target pulmonary vessels, thus increasing the ability of the RV to withstand increased afterload and reducing mortality. ITPP may be one such potential therapy.

Abstract 1099: Single-cell Transcriptomic And Epigenic Profiling Identifies Sox6 As A Key Regulator Of Arterial Endothelial Cell Phenotype In Systemic Sclerosis-associated Pulmonary Hypertension

Background: Pulmonary hypertension (PH) frequently arises as a complication of systemic sclerosis (SSc), and is a major cause of death among patients with this condition. Pulmonary vasculopathy in SSc is characterized by endothelial dysfunction with subsequent remodeling of the pulmonary vasculature, especially arterioles and small arteries. Characterization of transcriptional regulators driving the pathological changes in arterial endothelial cells (ECs) is critical to understanding pathogenic mechanisms underlying SSc-associated vasculopathy. Methods and Results: We performed single-cell multiome sequencing to simultaneously profile the transcriptome and epigenome of explanted lung tissue from SSc-PH patients (n = 9) and healthy donors (n = 6). We identified co-regulated genes and candidate enhancer regions associated with transcription factors (TFs) across different EC cell states using SCENIC+. Gene regulatory network analysis revealed SOX6 as a key transcription factor for the arterial EC phenotype associated with SSc-PH. 71 genes and 153 regions were predicted to be regulated by SOX6. Notably, SOX6 was the only SOX family member significantly upregulated in SSc-PH arterial ECs (fold change = 40.0, adjusted p-value = 6.1*10 -21 ). Putative bound TF motif instances accounting for chromatin accessibility in the candidate enhancer regions were identified using the base-resolution deep learning model, ChromBPNet. Consistent with SCENIC+ predictions, cell-state specific ChromBPNet models revealed higher putative TF occupancy at SOX motif instances across the genome. In addition, we identified SOX/ETS composite motif instances showing higher putative occupancy in SSc-PH arterial ECs, which may support cooperative binding of SOX proteins with ETS family members. Conclusions: These data provide novel insight into transcriptional regulatory programs of arterial ECs in SSc-PH and highlight SOX6 as a key contributor.

Neurophysiological Mechanisms of Exertional Dyspnea in Patient’s Post-Pulmonary Embolism: The Effect of Inhaled Nitric Oxide

Following pulmonary embolism (PE), up to a third of patients develop persistent activity-related dyspnea, even in those without chronic thromboembolic pulmonary hypertension (CTEPH). It has been shown that heightened exertional dyspnea in patients post-PE (without CTEPH) is linked to greater inspiratory neural drive (IND) during exercise. The heightened IND, in turn, is secondary to increased physiological dead space (VD/VT) and greater ventilatory requirements for CO2 (VE/VCO2). The reasons for the increased VD/VT and VE/VCO2 are unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Thus, the current study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower exertional IND and dyspnea, and improve exercise endurance in patients post-PE. In turn, the reduced IND and dyspnea would be linked to reductions in VD/VT and VE/VCO2. In this randomized, double-blind, placebo-controlled crossover study, 14 clinically stable patients with chronic activity related dyspnea post-PE (without evidence of PH) completed symptom-limited constant work rate cycle exercise tests while breathing iNO (40 ppm) or placebo (21% O2), on separate days. IND (assessed by diaphragm electromyography), VD/VT and VE/VCO2 (expired and arterialized blood gas), and dyspnea intensity (modified Borg 0-10 scale) were compared throughout exercise. At rest, right-ventricular systolic pressure (RVSP) with placebo or iNO was estimated by echocardiography. At the highest individual standardized exercise time (5.8±2.0 min), iNO decreased VD/VT (0.22±0.09 vs 0.27±0.07, p=0.02), VE/VCO2 (33.0±3.5 vs 34.5±3.8 units, p=0.04), IND (48.8±10.3 vs 57.6±11.8 %, p=0.02) and dyspnea intensity (3.0±1.0 vs 4.0±1.4 Borg units, p&lt;0.01), compared with placebo. Throughout exercise, estimated alveolar ventilation, O2 saturation, O2 pulse and operating lung volumes were unaffected by iNO (all p&gt;0.05). iNO increased exercise endurance time (8.1±3.5 vs 6.5±2.3 min, p&lt;0.001), compared with placebo. iNO reduced resting RVSP by 2.5±2.0 mmHg. iNO decreased exertional IND and dyspnea, and improved exercise endurance in patients with post-PE. The reduced IND, in turn, may be linked to decreased VD/VT and VE/VCO2, reflecting improved ventilation/perfusion. These data provide preliminary evidence of a partially reversible pulmonary vasculopathy, that contributes to dyspnea and exercise limitation in symptomatic patients post-PE. Queen’s University Spear Endowment Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mechanisms of Pulmonary Vasculopathy in Acute and Long-Term COVID-19: A Review.

Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID.

Predominance of M2 macrophages in organized thrombi in chronic thromboembolic pulmonary hypertension patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease characterized by thrombotic occlusion of pulmonary arteries and vasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. Thrombotic lesions in CTEPH contain CD68+ macrophages, and increasing evidence supports their role in disease pathogenesis. Macrophages are classically divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which are involved in wound healing and tissue repair. Currently, the phenotype of macrophages and their localization within thrombotic lesions of CTEPH are largely unknown. In our study, we subclassified thrombotic lesions of CTEPH patients into developing fresh thrombi (FT) and organized thrombi (OT), based on the degree of fibrosis and remodeling. We used multiplex immunofluorescence histology to identify immune cell infiltrates in thrombotic lesions of CPTEH patients. Utilizing software-assisted cell detection and quantification, increased proportions of macrophages were observed in immune cell infiltrates of OT lesions, compared with FT. Strikingly, the proportions with a CD206+INOS- M2 phenotype were significantly higher in OT than in FT, which mainly contained unpolarized macrophages. Taken together, we observed a shift from unpolarized macrophages in FT toward an expanded population of M2 macrophages in OT, indicating a dynamic role of macrophages during CTEPH pathogenesis.

Pulmonary Hypertension in Connective Tissue Diseases Other than Systemic Sclerosis.

Pulmonary hypertension (PH) is a known complication of certain connective tissue diseases (CTDs), with systemic sclerosis (SSc) being the most common in the Western world. However, PH in association with non-SSc CTD such as systemic lupus erythematous, mixed connective tissue disease, and primary Sjögren's syndrome constitutes a distinct subset of patients with inherently different epidemiologic profiles, pathophysiologic mechanisms, clinical features, therapeutic options, and prognostic implications. The purpose of this review is to inform a practical approach for clinicians evaluating patients with non-SSc CTD-associated PH.The development of PH in these patients involves a complex interplay between genetic factors, immune-mediated mechanisms, and endothelial cell dysfunction. Furthermore, the broad spectrum of CTD manifestations can contribute to the development of PH through various pathophysiologic mechanisms, including intrinsic pulmonary arteriolar vasculopathy (pulmonary arterial hypertension, Group 1 PH), left-heart disease (Group 2), chronic lung disease (Group 3), chronic pulmonary artery obstruction (Group 4), and unclear and/or multifactorial mechanisms (Group 5). The importance of diagnosing PH early in symptomatic patients with non-SSc CTD is highlighted, with a review of the relevant biomarkers, imaging, and diagnostic procedures required to establish a diagnosis.Therapeutic strategies for non-SSc PH associated with CTD are explored with an in-depth review of the medical, interventional, and surgical options available to these patients, emphasizing the CTD-specific considerations that guide treatment and aid in prognosis. By identifying gaps in the current literature, we offer insights into future research priorities that may prove valuable for patients with PH associated with non-SSc CTD.

Overnight desaturation in interstitial lung diseases: links to pulmonary vasculopathy and mortality.

Overnight desaturation predicts poor prognosis across interstitial lung diseases (ILDs). The aim of the present study was to investigate whether nocturnal desaturation is associated with pulmonary vasculopathy and mortality. A retrospective single centre study of 397 new ILD patients was carried out including patients with idiopathic pulmonary fibrosis (IPF) (n=107) and patients with non-IPF fibrotic ILD (n=290). This is the largest study to date of the effect of significant nocturnal desaturation (SND) (≥10% of total sleep time with oxygen saturation ≤90% measured by pulse oximetry). The prevalence of SND was 28/107 (26.2%) in IPF and 80/290 (27.6%) in non-IPF ILD. The prevalence of SND was higher in non-IPF ILDs than in IPF (p=0.025) in multivariate analysis. SND was associated with noninvasive markers of pulmonary hypertension (PH): tricuspid regurgitation velocity (TRV) (p<0.0001), brain natriuretic peptide (p<0.007), carbon monoxide transfer coefficient (p<0.0001), A-a gradient (p<0.0001), desaturation >4% in 6-min walking test (p<0.03) and pulmonary artery diameter (p<0.005). SND was independently associated with high echocardiographic PH probability in the entire cohort (OR 2.865, 95% CI 1.486-5.522, p<0.002) and in non-IPF fibrotic ILD (OR 3.492, 95% CI 1.597-7.636, p<0.002) in multivariate analysis. In multivariate analysis, SND was associated with mortality in the entire cohort (OR 1.734, 95% CI 1.202-2.499, p=0.003) and in IPF (OR 1.908, 95% CI 1.120-3.251, p=0.017) and non-IPF fibrotic ILD (OR 1.663, 95% CI 1.000-2.819, p=0.041). Separate models with exclusion of each one of the diagnostic subgroups showed that no subgroup was responsible for this finding in non-IPF ILDs. SND was a stronger marker of 5-year mortality than markers of PH. SND was associated with high echocardiographic probability and mortality and was a stronger predictor of mortality in IPF and non-IPF ILDs grouped together to power the study.

Phenotypes of Sarcoidosis-Associated Pulmonary Hypertension-A Challenging Mystery.

Sarcoidosis has been a well-recognised risk factor for pulmonary hypertension (PH) for a long time, but still, the knowledge about this concatenation is incomplete. Sarcoidosis-associated PH (SAPH) is an uncommon but serious complication associated with increased morbidity and mortality among sarcoidosis patients. The real epidemiology of SAPH remains unknown, and its pathomechanisms are not fully explained. Sarcoidosis is a heterogeneous and dynamic condition, and SAPH pathogenesis is believed to be multifactorial. The main roles in SAPH development play: parenchymal lung disease with the destruction of pulmonary vessels, the extrinsic compression of pulmonary vessels by conglomerate masses, lymphadenopathy or fibrosing mediastinitis, pulmonary vasculopathy, LV dysfunction, and portal hypertension. Recently, it has been recommended to individually tailor SAPH management according to the predominant pathomechanism, i.e., SAPH phenotype. Unfortunately, SAPH phenotyping is not a straightforward process. First, there are gaps in our understanding of undergoing processes. Second, the assessment of such a pivotal element as pulmonary vasculature on a microscopic level is non-feasible in SAPH patients antemortem. Finally, SAPH is a dynamic condition, multiple phenotypes usually coexist, and patients can switch between phenotypes during the course of sarcoidosis. In this article, we summarise the basic knowledge of SAPH, describe SAPH phenotypes, and highlight some practical problems related to SAPH phenotyping.

Connective tissue disease-associated pulmonary hypertension: A comprehensive review.

Connective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno-occlusive disease, pulmonary venous hypertension, interstitial lung disease-associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%-12%. The most recent European Society of Cardiology/European Respiratory Societyguidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD-PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD-PAH are inferior to those of idiopathic PAH, with those of SSc-PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD-PAH, particularly SSc-PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD-PAH. Ultimately, a better understanding of the pathogenesis of CTD-PAH will be required to develop targeted therapies for this morbid condition.

The chest CT signs for pulmonary veno-occlusive disease correlate with pulmonary haemodynamics in systemic sclerosis.

Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.

Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study.

Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years. This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines.

Toxic and infectious lung injury differential diagnosis specifics in oncohematological patients

Background. Assessment of lung injury in oncohematological patients is a relevant problem, since the spectrum of pathological changes is wide and includes pulmonary infections, tumor cell infiltration, cardiogenic and non-cardiogenic pulmonary edema, bronchiolitis obliterans, interstitial pneumonitis, post-radiation and post-inflammatory pneumofibrosis, pulmonary vasculopathy and pleural effusion. At the moment there are no approved recommendations with criteria of differential diagnosis for these conditions, in particular, with differences between the most common therapy complication represented by pulmonary infections and poorly explored drug-induced toxic lesions.Aim. Identification of criteria for pneumotoxicity, allowing for differential diagnosis with pulmonary infections developing during chemotherapy, according to data routinely obtained in real clinical practice.Materials and methods. The study group included 38 patients with cytotoxic and autoimmune lung injury caused by specific therapy (group 1); the comparison group included 38 patients with infectious lesions receiving the same antitumor drugs (group 2). The data of the anamnesis, clinical course, instrumental studies and standard laboratory tests was studied retrospectively. For statistical analysis, the Mann–Whitney, χ2, Kruskal–Wallis tests were used. ROC analysis was performed to assess the sensitivity and specificity of various factors in relation to toxic damage.Results. Patients with lymphomas predominated in group of toxic lung injury (63 %). In patients who underwent allogeneic hematopoietic stem cells transplantation, toxic complications developed in the period from 35 to 1289 days, infectious – from 4 to 43 days. Statistically significant differences were obtained in the presence of a concomitant state of an altered immune response: 32 % of patients in the toxic lesion group versus 5 % in the infectious group had a history of allergy, and, in contrast to the infectious lesion group, in the toxic lesion group autoimmune diseases were detected. The main symptom in patients of the first group was shortness of breath, which was observed in 68 % of cases, of the second – an increased body temperature, observed in 92 % of cases; cough was also a common symptom – in 19 % and 13 % of patients respectively. In 58 % of patients of the second group, concomitant mucositis was detected, while in the first group this complication did not occur in any of them. The most common radiological pattern (71 % of cases in each group) was ground-glass opacities, in patients of the second group often combined with infiltrative changes and thickening of the bronchial walls (in 53 and 42 % of cases respectively). Among laboratory results, the largest differences between groups were observed in the leukocyte levels (with an average level of 2.5 . 109 / L in the infectious group versus 6 . 109 / L in the toxic group), eosinophils (with an average of 3.6 % in the toxic group versus 1.75 % in the infectious group), C-reactive protein (with an average level of 146.7 mg / L in the infectious group versus 52.4 mg / L in the toxic group), and creatinine (with an average of 0.085 mmol / L in the toxic group versus 0.071 mmol / L in the infectious group).Conclusion. The data obtained in this research indicates the value of taking an anamnesis and the importance of performing additional studies in patients with suspected drug-induced lung injury, as well as identifies risk groups. Based on the revealed differences, a scale for the differential diagnosis of drug-induced toxic and infectious lung damage, which includes the results of publicly available research methods, with high sensitivity and specificity, was proposed. Further research for more specific, but, at the same time, universal for various drugs, criteria for toxic lung damage is relevant.

Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity.

Pulmonary arterial hypertension (PAH) is a rare and severe disorder characterized by progressive pulmonary vasculopathy. Growth differentiation factor (GDF)2 encodes the pro-protein bone morphogenetic protein (BMP) 9, activated after cleavage by endoproteases into an active mature form. BMP9, together with BMP10, are high-affinity ligands of activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPR2). GDF2 mutations have been reported in idiopathic PAH with most patients being heterozygous carriers although rare homozygous cases have been described. The link between PAH occurrence and BMP9 or 10 expression level is still unclear. In this study, we describe a pediatric case of PAH also presenting with telangiectasias and epistaxis. The patient carries the novel homozygous GDF2 c.946A > G mutation, replacing the first arginine of BMP9's cleavage site (R316) by a glycine. We show that this mutation leads to an absence of circulating mature BMP9 and mature BMP9-10 heterodimers in the patient's plasma although pro-BMP9 is still detected at a similar level as controls. In vitro functional studies further demonstrated that the mutation R316G hampers the correct processing of BMP9, leading to the secretion of inactive pro-BMP9. The heterozygous carriers of the variant were asymptomatic, similarly to previous reports, reinforcing the hypothesis of modifiers preventing/driving PAH development in heterozygous carriers.

Abstract 220: Post-gwas Functional Genomics Analysis Of Abo Locus To Identify Novel Pathogenic Mechanisms For Chronic Thromboembolic Pulmonary Hypertension

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and mysterious complication of pulmonary embolism, characterized by chronic pulmonary arterial thrombosis, occlusions and vasculopathy. Emerging evidence has suggested genetic relevance of CTEPH, particularly to ABO blood type. Genome-wide association study (GWAS) has identified ABO gene as the most significant genetic locus associated with CTEPH. This locus, however, consists only intronic SNPs and there is no mechanistic explanation on how these non-coding SNPs control the risk of CTEPH. Methods: GWAS-identified CTEPH-associated ABO locus was analyzed, and haplotype SNPs were identified based on linkage disequilibrium (LD). Electrophoretic mobility shift assay (EMSA) was applied to screen functional SNPs (fSNPs) based on allele-imbalanced nuclear protein binding. SNP-binding nuclear transcription factors (TFs) were identified by proteomics. Hi-C chromatin-interaction analysis was utilized to determine potential target genes affected by fSNPs. Knockdown of fSNP-associated TFs in human pulmonary artery endothelial cells (hPAECs) was applied to validate the regulation of TFs on target genes. Results: Based on GWAS, the minor allele of tag SNP rs2519093 is associated with higher risk of CTEPH (Odds ratio 2.22). It defines 11 haplotype SNPs in a LD with R 2 &gt; 0.8. Screened by EMSA with hPAEC nuclear proteins, intronic SNPs rs579459 and rs550057 were identified functional given their allele-specific protein binding. Proteomics analysis identified 3 candidate TFs that allele-specifically bind to fSNP rs579459: PBX1, CTCF and SAFB2. Candidate target gene ADAMTS13 is chosen based on its prominent interaction with fSNP revealed by Hi-C analysis, and the potential role in thromboembolism through vWF cleavage. TF knockdown by siRNA downregulates ADAMTS13 in hPAECs, suggesting their regulatory function as activators. Conclusion: Leveraging our post-GWAS functional genomics approach, we identified fSNPs in ABO locus that define a genetic architecture controlling the susceptibility of CTEPH. This genetic architecture, along with the newly identified fSNP-associated TFs and target gene ADAMTS13, provides a biological explanation for the pathogenesis of CTEPH.