Status and Future Directions for Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Disease With and Without Pulmonary Hypertension: A Scientific Statement From the American Heart Association.

Balloon pulmonary angioplasty continues to gain traction as a treatment option for patients with chronic thromboembolic pulmonary disease with and without pulmonary hypertension. Recent European Society of Cardiology guidelines on pulmonary hypertension now give balloon pulmonary angioplasty a Class 1 recommendation for inoperable and residual chronic thromboembolic pulmonary hypertension. Not surprisingly, chronic thromboembolic pulmonary hypertension centers are rapidly initiating balloon pulmonary angioplasty programs. However, we need a comprehensive, expert consensus document outlining critical concepts, including identifying necessary personnel and expertise, criteria for patient selection, and a standardized approach to preprocedural planning and establishing criteria for evaluating procedural efficacy and safety. Given this lack of standards, the balloon pulmonary angioplasty skill set is learned through peer-to-peer contact and training. This document is a state-of-the-art, comprehensive statement from key thought leaders to address this gap in the current clinical practice of balloon pulmonary angioplasty. We summarize the current status of the procedure and provide a consensus opinion on the role of balloon pulmonary angioplasty in the overall care of patients with chronic thromboembolic pulmonary disease with and without pulmonary hypertension. We also identify knowledge gaps, provide guidance for new centers interested in initiating balloon pulmonary angioplasty programs, and highlight future directions and research needs for this emerging therapy.

Aberrant long-chain fatty acid metabolism associated with evolving systemic sclerosis-associated pulmonary arterial hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n = 22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared with metabolites assayed in matched SSc patients who did not develop PAH (n = 22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 yr) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to 2 yr before clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including before clinical diagnosis and in mild disease.NEW & NOTEWORTHY Abnormal lipid metabolism is evident across time in the development of SSc-PAH, and dysregulated long-chain fatty acid metabolism predicts overt PAH.

Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Pulmonary Arterial Hypertension in Connective Tissue Diseases Beyond Systemic Sclerosis.

Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) (CTD-PAH) is a devastating condition that may progress rapidly to cause right ventricular dysfunction, resulting in significant morbidity and mortality. The pathobiology, epidemiology, natural history, early diagnosis, and treatment response of PAH associated with scleroderma (SSc-PAH) have been the subjects of intense research efforts over the previous decade. The success of these efforts has resulted in increased awareness and earlier detection of SSc-PAH. Practitioners are less aware of the risk of PAH associated with other CTDs; the aim of this article is to discuss the broader scope of CTD-PAH.

Impact of the revised haemodynamic definition on the diagnosis of pulmonary hypertension in patients with systemic sclerosis.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). We explored the impact of the updated haemodynamic definition of pulmonary hypertension (PH), as proposed by the 6th World Symposium on Pulmonary Hypertension. METHODS: In this single-centre retrospective analysis, patients with SSc who had right heart catheterisation (RHC) were included. We compared the prior PH definition to the updated PH definition. The prior definition classified PH as mean pulmonary arterial pressure (mPAP) ≥25 mmHg and further divided into pre-capillary PH (PAH and PH due to lung disease and/or hypoxia), post-capillary PH, and combined pre- and post-capillary PH groups. For the updated definition, PH was classified as mPAP >20 mmHg and further divided into the different groups. We validated our findings in the DETECT cohort. RESULTS: Between 2005 and March 2019, 268 RHCs were performed in this single-centre cohort. Using the prior definition, 137 (51%) were diagnosed with PH, with 89 classified as pre-capillary PH (56 with PAH and 33 with PH due to lung disease and/or hypoxia), 29 as post-capillary PH, and 19 as combined pre- and post-capillary PH. When the updated definition was applied to the cohort, seven out of 131 (5%) with no PH were reclassified to pre-capillary PH (PAH (n=1), PH due to lung disease (n=3) and post-capillary PH (n=3)). In those with mPAP 21-24 mmHg, with no left heart or significant lung disease, one out of 28 (4%) in our cohort and four out of 36 (11%) in the DETECT cohort were reclassified as PAH. CONCLUSION: The updated PH definition does not appear to have a significant impact on the diagnosis of PH in two different screening cohorts.

Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting.

The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs.

Purinergic dysregulation in pulmonary hypertension.

Despite the fact that nucleotides and adenosine help regulate vascular tone through purinergic signaling pathways, little is known regarding their contributions to the pathobiology of pulmonary arterial hypertension, a condition characterized by elevated pulmonary vascular resistance and remodeling. Even less is known about the potential role that alterations in CD39 (ENTPD1), the ectonucleotidase responsible for the conversion of the nucleotides ATP and ADP to AMP, may play in pulmonary arterial hypertension. In this study we identified decreased CD39 expression on the pulmonary endothelium of patients with idiopathic pulmonary arterial hypertension. We next determined the effects of CD39 gene deletion in mice exposed to normoxia or normobaric hypoxia (10% oxygen). Compared with controls, hypoxic CD39(-/-) mice were found to have a markedly elevated ATP-to-adenosine ratio, higher pulmonary arterial pressures, more right ventricular hypertrophy, more arterial medial hypertrophy, and a pro-thrombotic phenotype. In addition, hypoxic CD39(-/-) mice exhibited a marked increase in lung P2X1 receptors. Systemic reconstitution of ATPase and ADPase enzymatic activities through continuous administration of apyrase decreased pulmonary arterial pressures in hypoxic CD39(-/-) mice to levels found in hypoxic CD39(+/+) controls. Treatment with NF279, a potent and selective P2X1 receptor antagonist, lowered pulmonary arterial pressures even further. Our study is the first to implicate decreased CD39 and resultant alterations in circulating purinergic signaling ligands and cognate receptors in the pathobiology of pulmonary arterial hypertension. Reconstitution and receptor blocking experiments suggest that phosphohydrolysis of purinergic nucleotide tri- and diphosphates, or blocking of the P2X1 receptor could serve as treatment for pulmonary arterial hypertension.

Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH. METHODS: We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations. RESULTS: The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present. CONCLUSION: We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

Tissue-resident ecto-5' nucleotidase (CD73) regulates leukocyte trafficking in the ischemic brain.

Ectoenzymes expressed on the surface of vascular cells and leukocytes modulate the ambient nucleotide milieu. CD73 is an ecto-5' nucleotidase that catalyzes the terminal phosphohydrolysis of AMP and resides in the brain on glial cells, cells of the choroid plexus, and leukocytes. Though CD73 tightens epithelial barriers, its role in the ischemic brain remains undefined. When subjected to photothrombotic arterial occlusion, CD73(-/-) mice exhibited significantly larger (49%) cerebral infarct volumes than wild-type mice, with concordant increases in local accumulation of leukocyte subsets (neutrophils, T lymphocytes, macrophages, and microglia). CD73(-/-) mice were rescued from ischemic neurologic injury by soluble 5'-nucleotidase. In situ, CD73(-/-) macrophages upregulated expression of costimulatory molecules far more than wild-type macrophages, with a sharp increase of the CD80/CD86 ratio. To define the CD73-bearing cells responsible for ischemic cerebroprotection, mice were subjected to irradiative myeloablation, marrow reconstitution, and then stroke following engraftment. Chimeric mice lacking CD73 in tissue had larger cerebral infarct volumes and more tissue leukosequestration than did mice lacking CD73 on circulating cells. These data show a cardinal role for CD73 in suppressing ischemic tissue leukosequestration. This underscores a critical role for CD73 as a modulator of brain inflammation and immune function.

Pulmonary Embolism Center of Excellence: Putting It All Together.

Center of excellence (COE) designations are generally used to identify programs with expertise in a specific area of medicine. Meeting criteria for a COE may result in advantages including improved clinical outcomes, marketing advantages, and improved financial performance. However, criteria for COE designations are highly variable, and they are granted by a wide variety of entities. The diagnosis and treatment of both acute pulmonary emboli and chronic thromboembolic pulmonary hypertension are disciplines that require multidisciplinary expertise, highly coordinated care, specialized technology and advanced skillsets gained through high patient volumes.

Safe and Effective Balloon Pulmonary Angioplasty in the Outpatient Setting: The Michigan Medicine Experience.

Background: Balloon pulmonary angioplasty (BPA) is currently performed at select centers worldwide, with the current standard of practice being postprocedural inpatient monitoring for 24 to 72 hours. We sought to evaluate the safety and efficacy of BPA in a cohort of patients with chronic thrombo-embolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH) and outline a protocol for implementation in the outpatient setting. Methods: All patients with distal, inoperable CTEPH, residual symptoms after pulmonary endarterectomy, or symptomatic CTEPD from July 1, 2020, to June 30, 2022, were evaluated by a multidisciplinary chronic thromboembolic pulmonary hypertension team for consideration of BPA. Patients undergoing each BPA session adhered to a regimented protocol developed and implemented at our institution. Safety and efficacy were retrospectively evaluated with a mean follow-up time of 8.5 months. Results: Eighteen patients underwent a total of 78 BPA sessions. Overall, there was a significant improvement in World Health Organization functional class and mean improvement in 6-minute walking distance of +67 m. Hemodynamic parameters significantly improved with a mean decrease in mean pulmonary artery pressure and pulmonary vascular resistance of 7.3 ± 5.8 mm Hg and 1.7 ± 1.5 Wood units, respectively (P <.05). Complication rates were low with 3 (3.9%) of 78 patients developing scant hemoptysis and 1 (1.3%) of 78 experiencing vascular injury requiring inpatient hospitalization. Conclusions: BPA is both safe and effective when implemented in the outpatient setting using a regimented protocol provided there are necessary contingencies in place.

Symptoms Suggestive of Postpulmonary Embolism Syndrome and Utilization of Diagnostic Testing.

Background: Persistent symptoms of chest pain, dyspnea, fatigue, lightheadedness, and/or syncope more than 3 months after an acute pulmonary embolism (PE) are collectively classified as postpulmonary embolism syndrome (PPES). Although PPES is increasingly recognized as an important long-term sequel of acute PE, its contemporary incidence is unclear. Furthermore, the utilization of diagnostic testing for further phenotypic characterization of these patients is unknown. This study aimed to define the incidence of PPES and evaluate the utilization of diagnostic tests among a national cohort of patients with PE. Methods: Retrospective cohort study was performed using the national administrative database, Clinformatics DataMart Database (Optum Insight), and included adult patients (18 years or older) with no history of acute PE or pulmonary hypertension, diagnosed with acute PE between October 1, 2016, and December 31, 2018. With acute PE event as the exposure, the incidence of symptoms consistent with PPES and diagnostic test utilization among patients with PPES were evaluated. Results: Of 21,297 incident patients with acute PE, 11,969 (56.2%) showed ≥1 symptom of PPES, which was new since their pre-PE baseline. New dyspnea was the most common and noted in 3268/15,203 (21.5%) patients, followed by new malaise or fatigue in 2894/15,643 (18.5%) patients. Among the 11,969 patients with PPES, 5128 (42.8%) received ≥1 diagnostic test, with 3242 (27%) receiving a computed tomography pulmonary angiogram, 2997 (25%) receiving an echocardiogram, and 325 (2.7%) received a ventilation-perfusion scan within 3-12 months after PE. Significantly lower use of diagnostic testing was noted in patients older than 65 years (adjusted odds ratio, 0.89; 95% CI, 0.81-0.98). Conclusions: Symptoms consistent with PPES are common after acute PE, occurring in more than half of the patients. Diagnostic imaging for further phenotypic characterization is used in less than half of such patients with PPES.

Transpulmonary amino acid metabolism in the sugen hypoxia model of pulmonary hypertension.

In pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation. In this study, we utilize the sugen/hypoxia (SuHx) rodent model of PAH to examine the RV, LV and MVEC intracellular metabolome (using targeted metabolomics) in normoxic and SuHx rats. We additionally validate key findings from our metabolomics experiments with data obtained from cell culture of normoxic and SuHx MVECs, as well as metabolomics of human serum samples from two different PAH patient cohorts. Taken together, our data, spanning rat serum, human serum and primary isolated rat MVECs reveal that: (1) key classes of amino acids (specifically, branched chain amino acids-BCAA) are lower in the pre-capillary (i.e., RV) serum of SuHx rats (and humans); (2) intracellular amino acid levels (in particular BCAAs) are increased in SuHx-MVECs; (3) there may be secretion rather than utilization of amino acids across the pulmonary microvasculature in PAH and (4) an oxidized glutathione gradient is present across the pulmonary vasculature, suggesting a novel fate for increased glutamine uptake (i.e., as a source of glutathione). in MVECs in PAH. In summary, these data reveal new insight into the shifts in amino acid metabolism occurring across the pulmonary circulation in PAH.

Periprocedural Complications With Balloon Pulmonary Angioplasty: Analysis of Global Studies.

BACKGROUND: Balloon pulmonary angioplasty (BPA) was introduced as a treatment modality for patients with inoperable, medically refractory chronic thromboembolic pulmonary hypertension decades ago; however, reports of high rates of pulmonary vascular injury have led to considerable refinement in procedural technique. OBJECTIVES: The authors sought to better understand the evolution of BPA procedure-related complications over time. METHODS: The authors conducted a systematic review of original articles published by pulmonary hypertension centers globally and performed a pooled cohort analysis of procedure-related outcomes with BPA. RESULTS: This systematic review identified 26 published articles from 18 countries worldwide from 2013 to 2022. A total of 1,714 patients underwent 7,561 total BPA procedures with an average follow up of 7.3 months. From the first period (2013-2017) to the second period (2018-2022), the cumulative incidence of hemoptysis/vascular injury decreased from 14.1% (474/3,351) to 7.7% (233/3,029) (P < 0.01); lung injury/reperfusion edema decreased from 11.3% (377/3,351) to 1.4% (57/3,943) (P < 0.01); invasive mechanical ventilation decreased from 0.7% (23/3,195) to 0.1% (4/3,062) (P < 0.01); and mortality decreased from 2.0% (13/636) to 0.8% (8/1,071) (P < 0.01). CONCLUSIONS: Procedure-related complications with BPA, including hemoptysis/vascular injury, lung injury/reperfusion edema, mechanical ventilation, and death, were less common in the second period (2018-2022), compared with first period (2013-2017), likely from refinement in patient and lesion selection and procedural technique over time.

Anatomical Variations in Pulmonary Arterial Branches in Patients Undergoing Evaluation for Chronic Thromboembolic Pulmonary Hypertension.

Background: Catheter-based interventions have emerged for both acute and chronic pulmonary thromboembolic disease. With this development and the need for segmental cannulation, anatomic understanding of pulmonary arterial segmental branch origination is important. We aim to describe the prevalence of different pulmonary arterial segmental branch origination patterns. Methods: This study included 179 consecutive patients who underwent bilateral nonselective invasive pulmonary angiography for the evaluation of chronic thromboembolic pulmonary hypertension. Results: In our study population (age, 59.0 ± 14.8 years, 55.3% female, 71% White), we found several anatomic variations of branches to the different lobes. These included 7 branching patterns in the right upper lobe, 3 in the right middle lobe, and 10 in the right lower lobe (4 patterns for the origin of the superior segmental artery and 6 for the origin of the basilar segmental arteries). On the left side, we found 8 patterns in the left upper lobe, with 5 involving lingular branches, and 9 in the left lower lobe (5 for the origin of the superior segmental artery and 4 for the basilar segmental pulmonary arteries). Although there were many variations, only 2-3 variations for each individual lobe accounted for >90% of the angiograms. Conclusions: Up to 3 anatomic branching patterns per lobe were noted to account for >90% of pulmonary artery branching variations in this study. This knowledge is not only useful for the interventionalist performing catheter-directed therapies but also for future research efforts that aim to standardize reporting of pulmonary angiographic findings.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Interventional Imaging Roadmap to Successful Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension.

Balloon pulmonary angioplasty (BPA) is an evolving treatment modality for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not candidates for pulmonary endarterectomy. Although several imaging modalities currently exist for evaluating CTEPH, their individual use, specifically in the clinical practice of BPA, has not been well described. In this article, we provide a preprocedural, intraprocedural, and postprocedural interventional imaging roadmap for safe and effective BPA performance in routine clinical practice. Preprocedural assessment includes transthoracic echocardiography for right ventricular assessment, ventilation/perfusion scan to identify pulmonary segments with the highest degree of hypoperfusion, cross-sectional chest imaging excluding alternative causes of mismatched defects and providing anatomic and perfusion imaging concurrently, and nonselective invasive pulmonary angiography for risk stratification of individual lesion subtypes. Intraprocedural assessment includes subselective segmental angiography (SSA) for delineating segmental and subsegmental branch anatomy, lesion identification, and vessel sizing. Intravascular ultrasound and optical coherence tomography serve as adjunctive intraprocedural tools for more accurate vessel sizing and lesion characterization when SSA alone is insufficient. Postprocedural considerations include chest radiography to monitor for immediate postprocedure complications and echocardiography for the interval assessment of the right ventricle on longer-term follow-up.

Performance of the DETECT Algorithm for Pulmonary Hypertension Screening in a Systemic Sclerosis Cohort.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). This study was undertaken to assess predictive accuracies of the DETECT algorithm and the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines in SSc patients who underwent right-sided heart catheterization (RHC) for pulmonary hypertension (PH) evaluation. METHODS: Patients with SSc who had diagnostic RHC, had no PH or had PAH, and had available data on variables to allow application of the DETECT and 2015 ESC/ERS guidelines were included for analysis. PH classification was based on hemodynamics using the 2018 revised criteria and extent of lung fibrosis shown on high-resolution computed tomography. Sensitivity and predictive accuracies of the DETECT algorithm and 2015 ESC/ERS guidelines were calculated, including analysis of subjects with a diffusing capacity for carbon monoxide (DLco) of ≥60% predicted. RESULTS: Sixty-eight patients with SSc had RHC, of whom 58 had no PH and 10 had PAH. The mean age was 60.0 years, and 58.8% had limited cutaneous SSc. The DETECT algorithm had a sensitivity of 1.00 (95% confidence interval [95% CI] 0.69-1.00) and a negative predictive value (NPV) of 1.00 (95% CI 0.80-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.80 (95% CI 0.44-0.97) and an NPV of 0.94 (95% CI 0.81-0.99). In patients with a DLco of ≥60% (n = 27), the DETECT algorithm had a sensitivity of 1.00 (95% CI 0.29-1.00) and an NPV of 1.00 (95% CI 0.59-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.67 (95% CI 0.09-0.99) and an NPV of 0.94 (95% CI 0.71-1.00). CONCLUSION: The DETECT algorithm has high sensitivity and NPV for diagnosis of PAH, including among individuals with a DLco of ≥60%.

Ecto-5' nucleotidase (CD73)-mediated adenosine generation and signaling in murine cardiac allograft vasculopathy.

Ecto-5'-nucleotidase (CD73) catalyzes the terminal phosphohydrolysis of 5'-adenosine monophosphate and is widely expressed on endothelial cells where it regulates barrier function. Because it is also expressed on lymphocytes, we hypothesized that it modulates vascular immune regulation under homeostatic conditions and dysregulation under stress conditions such as cardiac allotransplantation. In a heterotopic cardiac allotransplantation model, CD73 deficiency in either donors or recipients resulted in decreased graft survival and the development of cardiac allograft vasculopathy, suggesting a contribution of CD73 on both graft-resident and circulating cells in vasculopathy pathogenesis. Vascular perturbations incited by lack of CD73 included loss of graft barrier function and diminished graft expression of the A(2B) adenosine receptor (A(2B)AR), with a concordant exacerbation of the acute inflammatory and immune responses. The importance of CD73 in modulating endothelial-lymphocyte interaction was further demonstrated in allomismatched in vitro coculture experiments. Either genetic deletion or pharmacological blockade of CD73 increased transendothelial lymphocyte migration and inflammatory responses, suggesting that CD73 plays a critical role to suppress transendothelial leukocyte trafficking through its enzymatic activity. In addition, antagonism of A(2B)AR caused a significant increase in vascular leakage, and agonism of A(2B)AR resulted in marked prolongation of graft survival and suppression of cardiac allograft vasculopathy development. These data suggest a new paradigm in which phosphohydrolysis of adenosine monophosphate by CD73 on graft-resident or circulating cells diminishes transendothelial leukocyte trafficking and mitigates inflammatory and immune sequelae of cardiac transplantation via the A(2B)AR.