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The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype-phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle-cell disease (SCD), but its importance in children is less clear. The aim of this study was to define the incidence and causes of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54) were prospectively enrolled under basal conditions. Participants underwent echocardiography, pulse oximetry, 6-minute walk tests, and hematologic testing. Echocardiographic measures were compared between patients with SCD and control subjects before and after adjusting for hemoglobin. Correlations of echocardiographic and clinical parameters were determined. Tricuspid regurgitation velocity (TRV) was elevated compared to controls (2.28 vs 2.10 m/s, p <0.0001). Increased TRV was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial pressure. TRV remained elevated when controlling for left ventricular diameter and left atrial pressure. Echocardiographically derived pulmonary resistance was not significantly different between patients with SCD and controls, although it was elevated in the SCD subgroup with elevated TRV. When controlling for hemoglobin, TRV was no longer statistically different, but pulmonary insufficiency velocity, septal wall thickness, and estimated pulmonary resistance were statistically higher. TRV, pulmonary insufficiency end-diastolic velocity, and markers of increased cardiac output were correlated with indicators of adverse functional status, including history of acute chest syndrome, stroke, transfusions, and 6-minute walk distance. In conclusion, children with SCD had mildly increased TRV that was correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin-adjusted analysis also suggested a contribution of primary vascular changes. [ABSTRACT FROM AUTHOR]

The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1'). Thus, Group 1 of PAH is now more homogeneous. [ABSTRACT FROM AUTHOR]

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi-omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation-a hallmark of RBC aging-and lower post-transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling., Methods: Using skeletal muscle-specific Sirt3 knockout mice ( Sirt3 skm-/- ) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF., Results: Sirt3 skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3 skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3 skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF., Conclusions: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF., Competing Interests: M.T.G. is a coinventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for carbon monoxide poisoning, which have been licensed by Globin Solutions, Inc. M.T.G. is a shareholder, advisor, and director in Globin Solutions, Inc. M.T.G. is also coinventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and are now licensed to Globin Solutions and Hope Pharmaceuticals. M.T.G. is a principal investigator in an investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease.

Sickle cell disease (SCD) is associated with substantial morbidity and early mortality in afflicted adults. Cardiopulmonary complications that occur at increased frequency in SCD such as pulmonary embolism, pulmonary arterial hypertension, and acute chest syndrome can acutely worsen right ventricular function and lead to cardiogenic shock. Mechanical circulatory support including venoarterial extracorporeal membrane oxygenation (VA ECMO) is being increasingly utilized to treat hemodynamic collapse in various patient populations. However, a paucity of literature exists to guide the use of mechanical circulatory support in adults with SCD where disease-related sequela and unique hematologic aspects of this disorder may complicate extracorporeal therapy and must be understood. Here, we review the literature and describe three cases of adult patients with SCD who developed cardiogenic shock from acute decompensated right heart failure and were treated clinically with VA ECMO. Using an in vitro ECMO system, we investigate a potential increased risk of systemic fat emboli in patients with SCD who may be experiencing vaso-occlusive events with bone marrow involvement given the high-volume shunting of blood from venous to arterial systems with VA ECMO. The purpose of this study is to describe available extracorporeal life support experiences, review potential complications, and discuss the special considerations needed to further our understanding of the utility of VA ECMO in those with SCD., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease., Competing Interests: Dr. Gautam V. Ramani has served as a consultant for Merck and as a principal investigator for pharmaceutical studies with Janssen Pharmaceuticals and United Therapeutics. Dr. Mark T. Gladwin's work is supported by National Heart, Lung, and Blood Institute (NHLBI) Grant R01098032. Dr. Mark T. Gladwin is a coinventor of patents and patent applications directed to the use of recombinant neuroglobin and heme‐based molecules as antidotes for carbon monoxide poisoning, which have been licensed by Globin Solutions, Inc. Dr. Mark T. Gladwin is a shareholder, advisor, and director in Globin Solutions, Inc. Dr. Mark T. Gladwin is also coinventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and is now licensed to Globin Solutions and Hope Pharmaceuticals. Dr. Mark T. Gladwin was a principal investigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguate as a treatment for patients with sickle cell disease. Dr. Mark T. Gladwin is textbook author and receives royalties from MedMaster Inc. and is a textbook editor and receives royalties from McGraw‐Hill. Dr. Mark T. Gladwin is a paid consultant for Third Pole Therapeutics. The remaining authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation., (© 2024. The Author(s).)

Background: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events., Methods: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sβ-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed., Findings: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001)., Interpretation: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials., Funding: Bayer Pharmaceuticals., Competing Interests: Declaration of interests MTG is a co-inventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning, which have been licensed by Globin Solutions; is a shareholder, advisor, and director in Globin Solutions; is a co-inventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and is now licensed to Globin Solutions and Hope Pharmaceuticals; was a principal investigator in this investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease; and has previously served on Bayer HealthCare's Heart and Vascular Disease Research advisory board and previously on the Forma Therapeutics scientific advisory board. KIA has received research funding from Novartis, Novo Nordisk, and Takeda Pharmaceuticals; served on advisory boards for Novartis, Novo Nordisk, Agios Pharmaceuticals, Fulcrum Therapeutics, Pfizer, and Hillhurst Biopharmaceuticals; served as a consultant for Roche and Biomarin; and serves on a data monitoring committee for Vertex. AB is an equity holder in CRISPR Therapeutics. SAC served on a Pfizer advisory board. PCD reports research support from Novartis, Patient-Centered Outcomes Research Institute, National Institutes of Health, Food and Drug Administration, University of Pittsburgh, and University of Tennessee; consultancy for Vertex, Forma, Chiesi, and Speaker's Bureau for Novartis; and a pending patent for Point of Care Detection of Hemoglobin Sickling via Magnetic Fractionation. FER reports research funding from Novartis, Forma Therapeutics, and Agios. HJF reports research support from Merck, United Therapeutics, Cereno, and Janssen; and has served as a consultant for United Therapeutics, Janssen, Merck, Liquidia, and Sumitomo Pharma. GJK is an employee and equity holder in CSL Behring; is a co-inventor on a patent issued for a formulation of topical sodium nitrite, licensed to Emmaus Life Sciences; and previously served as a co-principal-investigator in this investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease. ESK is supported by grants N1UG3 HL143192–01A1 from the National Institutes for Health, 2UL1TR001430–05A1 from the National Center for Advancing Translational Sciences, and U1EMC27864–08–00 from the Health Resources and Services Administration; and receives research support from Bayer, Forma Therapeutics, Nov Nordisk, Novartis, and United Therapeutics. SL is the vice president of the National Alliance of Sickle Cell Centers; is a consultant for Pfizer and Novartis and served on an adjudication committee for Bluebird Bio and Novo Nordisk; has received research funding from Imara, Novartis, Takeda, CSL-Behring, Health Resources and Services Administration, Patient-Centered Outcomes Research Institute, and Alexion; and holds stocks through a trust in Pfizer and Teva. JL is a consultant for Forma Novo-Nordisk. EMN reports consultancies with Novo Nordisk, Shield Therapeutics and Chiesi Pharmaceuticals; and is on is an advisory board for Chiesi Pharmaceuticals, Novo Nordisk, and Shield Therapeutics. DL was a principal investigator and sub-investigator on clinical trials for the following companies between 2021 and 2023: Bioverativ, Celgene, Exact Sciences, Janssen Research and Development, Novartis, Sanofi-Aventis, Incyte, Takeda, Vifor Pharma, Global Blood Therapeutics, Forma Therapeutics, Novo Nordisk, Abbvie, Pfizer, and CSL Bering. CRM is the executive director of Food as Medicine Therapeutics; is on the scientific advisory board for Trility; is the inventor or co-inventor of several University of California San Francisco-Benioff Children's Hospital Oakland patents that include nutritional supplements for autism and apraxia (licensed to Lifetrients generating royalties); is an inventor or co-inventor of several Emory University School of Medicine patents or pending patents directed to the use of nutritional supplements for autism, coronaviruses, and kidney disease; is a consultant for Roche and CSL Behring; and is an editor for the sickle cell disease fever and sickle cell disease pain online reference for UpToDate. CM reports consultancies with Fulcrum, Sangamo, Sanguine, Pfizer, and Novo Nordisk; and served on an advisory board for CSL Behring, Alexion, Sanguine Bio, Bluebird Bio, Vertex, Pfizer, Agios, Novo Nordisk, and Fulcrum. WS reports consultancies with Alexion, Pfizer, Novartis, Agios, Novo-Nordisk, Bluebird Bio, and Vertex. JGT has received research funding from Bausch, Forma, Pfizer, and Vifer; and was a consultant for Bausch, Glycomimetics, and Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Donor genetic variation is associated with red blood cell (RBC) storage integrity and post-transfusion recovery. Our previous large-scale genome-wide association study demonstrated that the African G6PD deficient A- variant (rs1050828, Val68Met) is associated with higher oxidative hemolysis after cold storage. Despite a high prevalence of X-linked G6PD mutation in African American population (>10%), blood donors are not routinely screened for G6PD status and its importance in transfusion medicine is relatively understudied., Study Design and Methods: To further evaluate the functional effects of the G6PD A- mutation, we created a novel mouse model carrying this genetic variant using CRISPR-Cas9. We hypothesize that this humanized G6PD A- variant is associated with reduced G6PD activity with a consequent effect on RBC hemolytic propensity and post-transfusion recovery., Results: G6PD A- RBCs had reduced G6PD protein with ~5% residual enzymatic activity. Significantly increased in vitro hemolysis induced by oxidative stressors was observed in fresh and stored G6PD A- RBCs, along with a lower GSH:GSSG ratio. However, no differences were observed in storage hemolysis, osmotic fragility, mechanical fragility, reticulocytes, and post-transfusion recovery. Interestingly, a 14% reduction of 24-h survival following irradiation was observed in G6PD A- RBCs compared to WT RBCs. Metabolomic assessment of stored G6PD A- RBCs revealed an impaired pentose phosphate pathway (PPP) with increased glycolytic flux, decreasing cellular antioxidant capacity., Discussion: This novel mouse model of the common G6PD A- variant has impaired antioxidant capacity like humans and low G6PD activity may reduce survival of transfused RBCs when irradiation is performed., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Objective: To determine whether nitrite can enhance exercise training (ET) effects in heart failure with preserved ejection fraction (HFpEF)., Methods: In this multicenter, double-blind, placebo-controlled, randomized trial conducted at 1 urban and 9 rural outreach centers between November 22, 2016, and December 9, 2021, patients with HFpEF underwent ET along with inorganic nitrite 40 mg or placebo 3 times daily. The primary end point was peak oxygen consumption (VO 2 ). Secondary end points included Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS, range 0 to 100; higher scores reflect better health status), 6-minute walk distance, and actigraphy., Results: Of 92 patients randomized, 73 completed the trial because of protocol modifications necessitated by loss of drug availability. Most patients were older than 65 years (80%), were obese (75%), and lived in rural settings (63%). At baseline, median peak VO 2 (14.1 mL·kg -1 ·min -1 ) and KCCQ-OSS (63.7) were severely reduced. Exercise training improved peak VO 2 (+0.8 mL·kg -1 ·min -1 ; 95% CI, 0.3 to 1.2; P<.001) and KCCQ-OSS (+5.5; 95% CI, 2.5 to 8.6; P<.001). Nitrite was well tolerated, but treatment with nitrite did not affect the change in peak VO 2 with ET (nitrite effect, -0.13; 95% CI, -1.03 to 0.76; P=.77) or KCCQ-OSS (-1.2; 95% CI, -7.2 to 4.9; P=.71). This pattern was consistent across other secondary outcomes., Conclusion: For patients with HFpEF, ET administered for 12 weeks in a predominantly rural setting improved exercise capacity and health status, but compared with placebo, treatment with inorganic nitrite did not enhance the benefit from ET., Trial Registration: ClinicalTrials.gov identifier: NCT02713126., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Carbon monoxide (CO) poisoning leads to 50,000-100,000 emergency room visits and 1,500-2,000 deaths each year in the United States alone. Even with treatment, survivors often suffer from long-term cardiac and neurocognitive deficits, highlighting a clear unmet medical need for novel therapeutic strategies that reduce morbidity and mortality associated with CO poisoning. This review examines the prevalence and impact of CO poisoning and pathophysiology in humans and highlights recent advances in therapeutic strategies that accelerate CO clearance and mitigate toxicity. We focus on recent developments of high-affinity molecules that take advantage of the uniquely strong interaction between CO and heme to selectively bind and sequester CO in preclinical models. These scavengers, which employ heme-binding scaffolds ranging from organic small molecules to hemoproteins derived from humans and potentially even microorganisms, show promise as field-deployable antidotes that may rapidly accelerate CO clearance and improve outcomes for survivors of acute CO poisoning.