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Background: Preload insufficiency is an underrecognized cause of exercise intolerance identified during invasive cardiopulmonary exercise testing, and defined hemodynamically by decreased biatrial filling pressures, cardiac output, and oxygen consumption (V̇O 2 ) at peak effort. Patients with preload insufficiency, however, typically present with symptoms of dyspnea on exertion, and/or exercise intolerance at submaximal efforts, particularly when performing activities of daily living. The cardiopulmonary hemodynamics and physiology at submaximal work levels of preload insufficiency have not been previously investigated. We hypothesized that preload insufficiency hemodynamics exist along a continuum, with submaximal exercise values reflecting peak exercise cardiopulmonary hemodynamics., Methods: We compared submaximal cardiopulmonary hemodynamics, measured at anaerobic threshold, between preload insufficiency patients and age-matched controls referred for dyspnea but with normal exercise responses., Results: Our study included 66 patients: 41 with preload insufficiency and 25 controls. Preload insufficiency patients exhibit significantly reduced V̇O 2 , watts, and METS at submaximal levels compared to controls, alongside earlier anaerobic threshold achievement and similar heart rates at anaerobic threshold., Conclusions: These findings underscore the profound impact of preload insufficiency on submaximal exercise capacity, emphasizing the importance of its recognition and management. This insight sets the stage for further investigations into interventions targeting preload insufficiency at submaximal exercise levels to enhance both exercise performance and quality of life., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Invasive cardiopulmonary exercise testing (iCPET) is increasingly recognized as a critical diagnostic tool for assessing exercise intolerance and dyspnea. The manuscript highlights the iCPET program's diagnostic precision in identifying various cardiopulmonary disorders, offering insights into tailored treatment strategies. This guide aims to assist institutions in establishing their iCPET programs, addressing both the technical and administrative facets essential for success. The narrative is rooted in personal experiences, reflecting on the demanding, yet rewarding, journey of enhancing patient care through advanced diagnostic capabilities., Competing Interests: Disclosure Dr M.G. Risbano receives grant support for the iCPET program from Shadyside Hospital Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The direct Fick principle is the standard for calculating cardiac output (CO) to detect CO-dependent conditions like exercise pulmonary hypertension (ePH). Fick CO arterial incorporates arterial haemoglobin (Hb a ) and oxygen saturation ( S aO 2 ) with oxygen consumption from exercise testing, while Fick CO non-arterial substitutes mixed venous haemoglobin (Hb mv ) and peripheral oxygen saturation ( S pO 2 ) in the absence of an arterial line. The decision to employ an arterial catheter for exercise testing varies, and discrepancies in oxygen saturation and haemoglobin between arterial and non-arterial methods may lead to differences in Fick CO, potentially affecting ePH classification., Methods: We performed a retrospective analysis of 296 consecutive invasive cardiopulmonary exercise testing (iCPET) studies comparing oxygen saturation from pulse oximetry ( S pO 2 ) and radial arterial ( S aO 2 ), Hb a and Hb mv , and CO calculated with arterial (CO arterial ) and non-arterial (CO non-arterial ) values. We assessed the risk of misclassification of pre- and post-capillary ePH and data loss due to inaccurate S pO 2 ., Results: When considering all stages from rest to peak exercise, Hb a and Hb mv demonstrated high correlation, while S pO 2 and S aO 2 as well as CO arterial and CO non-arterial demonstrated low correlation. Data loss was significantly higher across all stages of exercise for S pO 2 (n=346/1926 (18%)) compared to S aO 2 (n=17/1923 (0.88%)). We found that pre- and post-capillary ePH were misclassified as CO non-arterial data (n=7/41 (17.1%) and n=2/23 (8.7%), respectively). Patients with scleroderma and/or Raynaud's (n=11/33 (33.3%)) and black patients (n=6/19 (31.6%)) had more S pO 2 data loss., Conclusion: Reliance upon S pO 2 during invasive exercise testing results in the misclassification of pre- and post-capillary ePH, and unmeasurable S pO 2 for black, scleroderma and Raynaud's patients can preclude accurate exercise calculations, thus limiting the diagnostic and prognostic value of invasive exercise testing without an arterial line., Competing Interests: Conflict of interest: M.G. Risbano reports grants from the Shadyside Hospital Foundation, royalties from Springer, and advisory board participation from Gilead and Liquidia. L. Campedelli and S.M. Nouraie report grants from the Shadyside Hospital Foundation., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (ClinicalTrials.gov: NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population., Methods: Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12., Results: In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure., Conclusions: The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD., Competing Interests: Conflict of interest: S.D. Nathan is a paid consultant for United Therapeutics. R.G. Argula reports advisory board consulting fees from United Therapeutics, Liquidia Inc., Merck Pharmaceuticals, Janssen and Accordant Health (CVS), and lecture honoraria from United Therapeutics, outside the submitted work. M.G. Trivieri reports advisory board participation with Janssen, outside the submitted work. B. Medarov reports lecture honoraria from Jensen Pharmaceuticals, outside the submitted work. A. Raina reports lecture honoraria from Merck and United Therapeutics, outside the submitted work. M.G. Risbano reports grants from Shadyside Foundation, royalties from Springer (Pulmonary Hypertension: Controversial and Emerging Topics), and advisory board participation with Gilead and Liquidia, outside the submitted work. T. Thenappan reports grants from United Therapeutics, Aerovate, Merck and Aria CV, and consulting fees from Merck and United Therapeutics, outside the submitted work. J.S. Soto reports grants, lecture honoraria, travel support and advisory board participation with GlaxoSmithKline and Genentech Pharmaceuticals, outside the submitted work. H. Bell, V. Lacasse, P. Sista, M. Di Marino, A. Smart, B. Hawkes and E. Nelson are employees of United Therapeutics, the PERFECT study sponsor. T. Bull reports grants from Bayer, Merck, Insmed and Aerovate, lecture honoraria from Merck, payment for expert testimony from Lung Biotechnology, travel support from Lung, advisory board participation with Keros, consultancy for United Therapeutics and a leadership role as PHA SLC chair, outside the submitted work. V. Tapson is a paid consultant for United Therapeutics. A. Waxman reports grants from Aria CV PI, AI Therapeutics and Acceleron/Merck, consultancy for United Therapeutics, and data and safety monitoring board participation with Insmed, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease., Competing Interests: Declaration of interests S.Y.C. has served as a consultant for Merck, Janssen, and United Therapeutics. S.Y.C. is a director, officer, and shareholder in Synhale Therapeutics. S.Y.C. has held research grants from WoodNext, Bayer, and United Therapeutics. S.Y.C. and T.B. have filed patent applications regarding the targeting of metabolism in pulmonary hypertension. G.Y., Z.-K.Y., and O.O. are listed as inventors in patents not related to this work, which are filed by MSKCC. O.O. receives royalties from MSKCC, Johnson & Johnson, Jazz, and Y-mAbs and owns shares in Angiogenex, for which he is an unpaid member of the SAB, all of which are not related to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present a novel computer algorithm to automatically detect and segment pulmonary embolisms (PEs) on computed tomography pulmonary angiography (CTPA). This algorithm is based on deep learning but does not require manual outlines of the PE regions. Given a CTPA scan, both intra- and extra-pulmonary arteries were firstly segmented. The arteries were then partitioned into several parts based on size (radius). Adaptive thresholding and constrained morphological operations were used to identify suspicious PE regions within each part. The confidence of a suspicious region to be PE was scored based on its contrast in the arteries. This approach was applied to the publicly available RSNA Pulmonary Embolism CT Dataset (RSNA-PE) to identify three-dimensional (3-D) PE negative and positive image patches, which were used to train a 3-D Recurrent Residual U-Net (R2-Unet) to automatically segment PE. The feasibility of this computer algorithm was validated on an independent test set consisting of 91 CTPA scans acquired from a different medical institute, where the PE regions were manually located and outlined by a thoracic radiologist (>18 years' experience). An R2-Unet model was also trained and validated on the manual outlines using a 5-fold cross-validation method. The CNN model trained on the high-confident PE regions showed a Dice coefficient of 0.676±0.168 and a false positive rate of 1.86 per CT scan, while the CNN model trained on the manual outlines demonstrated a Dice coefficient of 0.647±0.192 and a false positive rate of 4.20 per CT scan. The former model performed significantly better than the latter model (p<0.01). The promising performance of the developed PE detection and segmentation algorithm suggests the feasibility of training a deep learning network without dedicating significant efforts to manual annotations of the PE regions on CTPA scans., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jiantao Pu reports financial support was provided by National Cancer Institute. Stephen Yu-Wah Chan reports financial support was provided by American Heart Association. Jiantao Pu reports financial support was provided by National Center for Complementary and Integrative Health. Dr. Stephen Yu-Wah Chan (SYC) has served as a consultant for Acceleron Pharma and United Therapeutics; SYC has held research grants from Actelion, Bayer, and Pfizer. SYC is a director, officer, and shareholder of Synhale Therapeutics. SYC has filed patents regarding metabolic dysregulation in pulmonary hypertension. The other authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We present a novel integrative computerized solution to automatically identify and differentiate pulmonary arteries and veins depicted on chest computed tomography (CT) without iodinated contrast agents. We first identified the central extrapulmonary arteries and veins using a convolutional neural network (CNN) model. Then, a computational differential geometry method was used to automatically identify the tubular-like structures in the lungs with high densities, which we believe are the intrapulmonary vessels. Beginning with the extrapulmonary arteries and veins, we progressively traced the intrapulmonary vessels by following their skeletons and differentiated them into arteries and veins. Instead of manually labeling the numerous arteries and veins in the lungs for machine learning, this integrative strategy limits the manual effort only to the large extrapulmonary vessels. We used a dataset consisting of 120 chest CT scans acquired on different subjects using various protocols to develop, train, and test the algorithms. Our experiments on an independent test set (n = 15) showed promising performance. The computer algorithm achieved a sensitivity of ∼98% in labeling the pulmonary artery and vein branches when compared with a human expert's results, demonstrating the feasibility of our computerized solution in pulmonary artery/vein labeling., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Rationale: Unproven theories abound regarding the long-range uptake and endocrine activity of extracellular blood-borne microRNAs into tissue. In pulmonary hypertension (PH), microRNA-210 (miR-210) in pulmonary endothelial cells promotes disease, but its activity as an extracellular molecule is incompletely defined., Objective: We investigated whether chronic and endogenous endocrine delivery of extracellular miR-210 to pulmonary vascular endothelial cells promotes PH., Methods and Results: Using miR-210 replete (wild-type [WT]) and knockout mice, we tracked blood-borne miR-210 using bone marrow transplantation and parabiosis (conjoining of circulatory systems). With bone marrow transplantation, circulating miR-210 was derived predominantly from bone marrow. Via parabiosis during chronic hypoxia to induce miR-210 production and PH, miR-210 was undetectable in knockout-knockout mice pairs. However, in plasma and lung endothelium, but not smooth muscle or adventitia, miR-210 was observed in knockout mice of WT-knockout pairs. This was accompanied by downregulation of miR-210 targets ISCU (iron-sulfur assembly proteins)1/2 and COX10 (cytochrome c oxidase assembly protein-10), indicating endothelial import of functional miR-210. Via hemodynamic and histological indices, knockout-knockout pairs were protected from PH, whereas knockout mice in WT-knockout pairs developed PH. In particular, pulmonary vascular engraftment of miR-210-positive interstitial lung macrophages was observed in knockout mice of WT-knockout pairs. To address whether engrafted miR-210-positive myeloid or lymphoid cells contribute to paracrine miR-210 delivery, we studied miR-210 knockout mice parabiosed with miR-210 WT; Cx3cr1 knockout mice (deficient in myeloid recruitment) or miR-210 WT; Rag1 knockout mice (deficient in lymphocytes). In both pairs, miR-210 knockout mice still displayed miR-210 delivery and PH, thus demonstrating a pathogenic endocrine delivery of extracellular miR-210., Conclusions: Endogenous blood-borne transport of miR-210 into pulmonary vascular endothelial cells promotes PH, offering fundamental insight into the systemic physiology of microRNA activity. These results also describe a platform for RNA-mediated crosstalk in PH, providing an impetus for developing blood-based miR-210 technologies for diagnosis and therapy in this disease.

Background: Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressures and is managed by vasodilator therapies. Current guidelines encourage PAH management in specialty care centers (SCCs), but evidence is sparse regarding improvement in clinical outcomes and correlation to vasodilator use with referral., Research Question: Is PAH management at SCCs associated with improved clinical outcomes?, Study Designand Methods: A single-center, retrospective study was performed at the University of Pittsburgh Medical Center (UPMC; overseeing 40 hospitals). Patients with PAH were identified between 2008 and 2018 and classified into an SCC or non-SCC cohort. Cox proportional hazard modeling was done to compare for all-cause mortality, as was negative binomial regression modeling for hospitalizations. Vasodilator therapy was included to adjust outcomes., Results: Of 580 patients with PAH at UPMC, 455 (78%) were treated at the SCC, comprising a younger (58.8 vs 64.8 years; P < .001) and more often female (68.4% vs 51.2%; P < .001) population with more comorbidities without differences in race or income. SCC patients demonstrated improved survival (hazard ratio, 0.68; P = .012) and fewer hospitalizations (incidence ratio, 0.54; P < .001), and provided more frequent disease monitoring. Early patient referral to SCC (< 6 months from time of diagnosis) was associated with improved outcomes compared with non-SCC patients. SCC patients were more frequently prescribed vasodilators (P < .001) and carried more diagnostic PAH coding (P < .001). Vasodilators were associated with improved outcomes irrespective of location but without statistical significance when comparing between locations (P > .05)., Interpretation: The UPMC SCC demonstrated improved outcomes in mortality and hospitalizations. The SCC benefit was multifactorial, with more frequent vasodilator therapy and disease monitoring. These findings provide robust evidence for early and regular referral of patients with PAH to SCCs., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Exercise pulmonary hypertension is an underappreciated form of physical limitation related to early pulmonary vascular disease. A low diffusing capacity of lungs for carbon monoxide (DLco) can be seen in patients with resting pulmonary hypertension as well as parenchymal lung disease. It remains unclear whether low DLco% identifies early pulmonary vascular disease. We hypothesize that a reduced DLco% differentiates the presence of exercise pulmonary hypertension in patients with parenchymal lung disease. Fifty-six patients referred for unexplained exertional dyspnea with pulmonary function tests within six months of hemodynamic testing underwent exercise right heart catheterization. Exclusion criteria included resting pulmonary arterial or venous hypertension. Receiver operator characteristic curve determined the optimal DLco% cutoffs based on the presence or absence of parenchymal lung disease. Twenty-one (37%) patients had parenchymal lung disease, most common manifesting as chronic obstructive lung disease or interstitial lung disease. In patients with parenchymal lung disease, a DLco of 46% demonstrated 100% sensitivity and 73% specificity for detecting exercise pulmonary hypertension. In patients without parenchymal lung disease, a DLco of 73% demonstrated 58% sensitivity and 94% specificity for detecting exercise pulmonary hypertension. In both cohorts, DLco% below the optimum cutoffs were associated with higher peak mean pulmonary arterial pressure and peak total pulmonary resistance consistent with the hemodynamic definition of exercise pulmonary hypertension. Patients with a DLco < 46% were more often treated with pulmonary vasodilators and had a trend to higher mortality and lung transplant. DLco% is a simple non-invasive screening test for the presence of exercise pulmonary hypertension in our mixed referral population with progressive exertional dyspnea. DLco < 46% with parenchymal lung disease and DLco < 73% without parenchymal lung disease may play a role in differentiating the presence of pulmonary vascular disease prior to invasive hemodynamic testing., (© The Author(s) 2020.)

Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator-activated receptor γ (PPARγ) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARγ agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post-transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARγ agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve "repurposing" or "repositioning" of pioglitazone for the treatment of clinical PAH.

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06-0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.

Cold storage of blood for 5 to 6 weeks has been shown to impair endothelial function after transfusion and has been associated with measures of end-organ dysfunction. Although the products of hemolysis, such as cell-free plasma hemoglobin, arginase, heme, and iron, in part mediate these effects, a complete analysis of transfused metabolites that may affect organ function has not been evaluated to date. Blood stored for either 5 or 42 days was collected from 18 healthy autologous volunteers, prior to and after autologous transfusion into the forearm circulation, followed by metabolomics analyses. Significant metabolic changes were observed in the plasma levels of hemolytic markers, oxidized purines, plasticizers, and oxidized lipids in recipients of blood stored for 42 days, compared with 5 days. Notably, transfusion of day 42 red blood cells (RBCs) increased circulating levels of plasticizers (diethylhexyl phthalate and derivatives) by up to 18-fold. Similarly, transfusion of day 42 blood significantly increased circulating levels of proinflammatory oxylipins, including prostaglandins, hydroxyeicosatrienoic acids (HETEs), and dihydroxyoctadecenoic acids. Oxylipins were the most significantly increasing metabolites (for 9-HETE: up to ∼41-fold, P = 3.7e-06) in day 42 supernatants. Measurements of arginine metabolism confirmed an increase in arginase activity at the expense of nitric oxide synthesis capacity in the bloodstream of recipients of day 42 blood, which correlated with measurements of hemodynamics. Metabolic changes in stored RBC supernatants impact the plasma metabolome of healthy transfusion recipients, with observed increases in plasticizers, as well as vasoactive, pro-oxidative, proinflammatory, and immunomodulatory metabolites after 42 days of storage., (© 2019 by The American Society of Hematology.)

Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional limitation. Despite normal resting pulmonary artery pressures, patients with ePH demonstrate early pulmonary vascular changes with reduced pulmonary arterial compliance (PAC) and vascular distensibility (α). Recent data suggest that targeted vasodilator therapy may improve hemodynamics in ePH, but it is not well-known whether such medications alter pulmonary vascular distensibility. Thus, we sought to evaluate if vasodilator therapy improved α a marker of early pulmonary vascular disease in ePH. Ten patients performed supine exercise right heart catheterization (exRHC) with bicycle ergometer to peak exercise. Patients diagnosed with ePH were treated with pulmonary vasodilators. A repeat symptom-limited exercise RHC was performed at least six months after therapy. Patients with ePH had evidence of early pulmonary vascular disease, as baseline PAC and α were reduced. After pulmonary vasodilator therapy, a number of peak exercise hemodynamics statistically improved, including a decrease of total pulmonary resistance and pulmonary vascular resistance, while cardiac output increased. Importantly, vasodilator therapy partially reversed the pathogenic decreases of α at the time of repeat exRHC. Pulmonary vascular distensibility, α, a marker of early pulmonary vascular disease, improves in ePH after therapy with pulmonary vasodilators.

Pulmonary arterial hypertension (PAH) is a progressive disease defined by an elevation in pulmonary arterial pressure that can lead to right heart failure and death. Ambrisentan is a selective endothelin receptor antagonist approved for the treatment of idiopathic, heritable PAH and connective tissue disease-associated PAH. Ambrisentan has been shown to improve exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with phosphodiesterase-5 inhibitors. In the recent randomized trial, AMBITION, it was shown that upfront combination therapy of ambrisentan and tadalafil significantly decreased the risk of clinical failure compared with monotherapy. This review describes the drug profile of ambrisentan and its safety and efficacy in the treatment of PAH.

Rationale: A major abnormality that characterizes the red cell "storage lesion" is increased hemolysis and reduced red cell lifespan after infusion. Low levels of intravascular hemolysis after transfusion of aged stored red cells disrupt nitric oxide (NO) bioavailabity, via accelerated NO scavenging reaction with cell-free plasma hemoglobin. The degree of intravascular hemolysis post-transfusion and effects on endothelial-dependent vasodilation responses to acetylcholine have not been fully characterized in humans., Objectives: To evaluate the effects of blood aged to the limits of Food and Drug Administration-approved storage time on the human microcirculation and endothelial function., Methods: Eighteen healthy individuals donated 1 U of leukopheresed red cells, divided and autologously transfused into the forearm brachial artery 5 and 42 days after blood donation. Blood samples were obtained from stored blood bag supernatants and the antecubital vein of the infusion arm. Forearm blood flow measurements were performed using strain-gauge plethysmography during transfusion, followed by testing of endothelium-dependent blood flow with increasing doses of intraarterial acetylcholine., Measurements and Main Results: We demonstrate that aged stored blood has higher levels of arginase-1 and cell-free plasma hemoglobin. Compared with 5-day blood, the transfusion of 42-day packed red cells decreases acetylcholine-dependent forearm blood flows. Intravascular venous levels of arginase-1 and cell-free plasma hemoglobin increase immediately after red cell transfusion, with more significant increases observed after infusion of 42-day-old blood., Conclusions: We demonstrate that the transfusion of blood at the limits of Food and Drug Administration-approved storage has a significant effect on the forearm circulation and impairs endothelial function. Clinical trial registered with www.clinicaltrials.gov (NCT 01137656).

All forms of WHO Group 1 PAH share a progressive and complex vasculopathy. At the center of this derangement lies the pulmonary vascular endothelium, which plays a crucial role in maintaining a delicate and precise balance of opposing vasoconstricting and vasodilating forces. In PAH, endothelial cell damage and dysfunction alter vascular homeostasis in favor of vasoconstriction. There is evidence of increased expression and activity in the vasoconstrictor and mitogen endothelin-1 signaling system and a decreased production of the potent vasodilator prostacyclin. These pathways have been a major focus of FDA approved PAH-specific therapies. Beyond these pathways, there is the dysfunction within the endothelial nitric oxide (NO) synthase signaling pathway and dysregulation of reactive oxygen and nitrogen species (ROS) that contribute to the pathogenesis of PAH. The dysregulation of vasodilator systems in PAH in large part involves the NO pathway, with almost every step subject to impairments. This includes a reduction in endothelial NO synthase function (eNOS), the enzymatic "uncoupling" of eNOS, increased scavenging of NO by superoxide and cell-free hemoglobin, the elaboration of endogenous competitive inhibitors of eNOS (ADMA), and the oxidation of the NO target, soluble guanylyl cyclase. The dysregulation of NO signaling pathways occurs in the setting of parallel upregulation of vascular oxidases that generate ROS. Enzymatic sources of ROS in PH that have been identified include the NAPDPH oxidases 1, 2, and 4, xanthine oxidase, uncoupled eNOS, and complex III of the mitochondrial electron transport chain. Superoxide produced from these sources reacts with NO to form the reactive nitrogen species peroxynitrate, further diverting bioavailable NO to more injuries species. In PAH, this upstream dysregulation of ROS/NO redox homeostasis severely impairs vascular tone and contributes to the pathological activation of mitogenic pathways, leading to cellular proliferation and obliteration of the pulmonary vasculature. Therapeutic strategies are being evaluated that target the associated dysregulated redox equilibrium and endothelial dysfunction in PAH. Therapeutic interventions reviewed in this chapter include NO donor or NO generating drugs, therapies that recouple eNOS or directly increase cGMP levels via inhibition of phosphodiesterase 5 or stimulation of soluble guanylyl cyclase, and therapies that inhibit vascular oxidases or scavenge ROS.

Background: Growth differentiation factor (GDF)-15 is a secreted member of the transforming growth factor-β cytokine superfamily. GDF-15 levels are elevated in the serum of patients with cardiovascular diseases. We hypothesized that GDF-15 levels would also be increased in the plasma and lung tissue of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH)., Methods: GDF-15 levels were measured in plasma in subjects with SSc-PAH (n = 30) and compared with subjects with systemic sclerosis (SSc) without pulmonary arterial hypertension (PAH) (n = 24). Patients with idiopathic PAH (IPAH) (n = 44) and normal individuals (n = 13) served as control subjects. Immunohistochemistry and immunofluorescence assay identified GDF-15 protein in lung tissue from patients with SSc-PAH and IPAH., Results: Patients with SSc-PAH had significantly higher mean circulating levels of GDF-15 in plasma compared with patients with SSc without PAH (422.3 ± 369.5 pg/mL vs 108.1 ± 192.8 pg/mL, P = .004). GDF-15 levels correlated positively with estimated right ventricular systolic pressure on echocardiogram and plasma levels of the amino terminal propeptide form of brain natriuretic peptide. There was an inverse correlation between circulating GDF-15 and diffusing capacity of the lung for carbon monoxide (Dlco) and a positive correlation with the FVC to Dlco ratio on pulmonary function test. GDF-15 levels > 125 pg/mL were associated with reduced survival. GDF-15 protein expression was increased in lung tissue from patients with SSc-PAH., Conclusions: GDF-15 may be a useful biomarker in PAH associated with SSc. Its presence in lung tissue may suggest a role in the pathology of the disease.

There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension.

Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease. Gene expression analysis was performed on a Microarray Cohort of scleroderma patients with (n = 10) and without (n = 10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a Validation Cohort of scleroderma patients with (n = 15) and without (n = 19) pulmonary hypertension by RT-qPCR. We identified inflammatory and immune-related genes including interleukin-7 receptor (IL-7R) and chemokine receptor 7 as differentially expressed in patients with scleroderma-associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL-7R on circulating CD4+ T-cells from scleroderma patients with pulmonary hypertension. Differences exist in the expression of inflammatory and immune-related genes in peripheral blood cells from patients with scleroderma-related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at-risk populations for early diagnosis and provide insight into mechanisms of scleroderma-related pulmonary hypertension., (© 2010 Wiley Periodicals, Inc.)