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Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit+ cells and severe pulmonary arterial hypertension. We detected c-kit+­ cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit+ α-smooth muscle actin+ cells and pulmonary arterial muscularization and did not affect c-kit+ von Willebrand Factor+ cell numbers. Both c-kit+ cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit+ α-smooth muscle actin+ cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit+ von Willebrand Factor+ cells is largely independent of CXC chemokine receptor 4. [ABSTRACT FROM AUTHOR]

Nutritional deficiencies have been described in patients with pulmonary arterial hypertension (PAH), such as in iron and vitamin D. However, an extensive description of vitamin and mineral status is lacking and until now there is no data on dietary intake in PAH patients. We analyzed blood samples and determined nutritional intake using a food frequency questionnaire (HELIUS) in a cohort of prevalent PAH patients at a single center in Amsterdam, the Netherlands. Quality of life (QoL) was assessed by the SF-36 questionnaire. In total, 37 patients were included (6 males, 31 females; 48 ± 16 years). The dietary intake of sugar was above 25 g in 87% of the patients and fluid intake was above 1500 ml in 78% of the patients. Sodium intake was below 1800 mg in the majority (56%) of the patients. Sugar and fluid intake were linear related. We confirm previously observed deficiencies of iron and vitamin D in our study population. In addition, we observed a functional vitamin B12 deficiency in 29% of patients, which coincided with an increased expression of methylmalonic acid. 60% of patients had a low vitamin K1 status (<0.8 nmol/L). Finally, 40% of patients had selenium levels below <100 μg/L and low selenium levels associated with reduced vitality in these patients. Besides the known deficiencies in iron and vitamin D levels, we observed in a subset of patients signs of vitamin B12, vitamin K1 and selenium deficiencies. There is room for improving dietary intake. Future research aims to demonstrate the clinical importance and reveal the effect of nutritional interventions. [ABSTRACT FROM AUTHOR]

The long-term outcomes of operated and nonoperated patients with chronic thromboembolic pulmonary hypertension were reported in a large, prospective, multicentre, European and Canadian registry. The long-term prognosis of operated patients was superior to that of nonoperated patients, indicating that surgery should be the first-choice treatment in this patient cohort. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3 , was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3′-deoxy-3′-[18F]-fluorothymidine (18FLT) using positron emission tomography. Methods and Results: We performed dynamic 18FLT positron emission tomography in 8 patients with idiopathic pulmonary arterial hypertension (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung 18FLT phosphorylation (k3) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086±0.034 versus 0.054±0.009 min−1; P <0.05). There was heterogeneity in the lung 18FLT signal both between patients with IPAH and within the lungs of each patient, compatible with histopathologic reports of lungs from patients with IPAH. Consistent with 18FLT positron emission tomographic data, TK1 (thymidine kinase 1) expression was evident in the remodeled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from patients with IPAH exhibited upregulated expression of TK1 and the thymidine transporter, ENT1 (equilibrative nucleoside transporter 1). In the monocrotaline and SuHx (Sugen hypoxia) rat pulmonary arterial hypertension models, increased lung 18FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent TK1 expression in remodeled vessels. Importantly, lung 18FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib. Conclusions: Dynamic 18FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in patients with IPAH. [ABSTRACT FROM AUTHOR]

The article presents a study that investigates the pathogenesis of pulmonary hypertension (PH) including the transition from adaptive right ventricular hypertrophy to right heart failure. It discusses the cardiac capillary loss in PH in rats using the Sugen model which uses the vascular endothelial growth factor (VEGF) receptor blocker SU5416 and the pulmonary artery banding (PAB) model that induces considerable pressure overload consistently while preserving the function of the right heart. It suggests that capillary rarefunction and endothelial dysfunction play an important role in the transition of adaptive right ventricular hypertrophy to right heart failure.

The aim of the UPHILL study (a nutrition and lifestyle intervention in patients with pulmonary arterial hypertension [PAH]: effect on quality of life [QoL]), was to determine the effect of innovative nutritional interventions on adjustments in nutritional intake and QoL. In this study a group of prevalent PAH patients at a single center in Amsterdam (the Netherlands) was informed about healthy nutrition using a newly designed video e-learning. They were subsequently instructed to follow a healthy diet during dietary intervention. Nutritional intake was assessed using a food frequency questionnaire (HELIUS) and QoL by the shortform (SF)-36 questionnaire. Nutritional parameters were determined in blood samples. Seventeen patients stable under treatment, who had been diagnosed with PAH 7.0 [3.0-14.0] years before, started and completed the intervention (2 males, 15 females; 45.35 ± 13.57 years). Since all patients in the intervention group made behavioral changes in nutritional intake, during study and follow-up, nutritional and lifestyle adaptations persisted. Despite the fact that patients had already high mean scores at baseline for both mental (74.10 [60.51-84.25]) and physical QoL (66.46 [50.21-73.84]), scores improved further during e-learning. Furthermore, patients who realized most nutritional adaptations, had the best improvement in QoL. This pilot study showed that e-learning modules on nutrition provide an unique opportunity to change nutritional intake in PAH patients and by that improve QoL. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?How does the interaction between posture and gravity affect the stresses on the lung, particularly in highly inflated gravitationally non‐dependent regions, which are potentially vulnerable to increased mechanical stress and injury?What is the main finding and its importance?Changes in stress attributable to gravity are not well characterized between postures. Using a new metric of gravitational stress, we show that regions of the lung near maximal inflation have the greatest gravitational stresses while supine, but not while prone. In simulations of increased lung weight consistent with severe pulmonary oedema, the prone lung has lower gravitational stress in vulnerable, non‐dependent regions, potentially protecting them from overinflation and injury. Prone posture changes the gravitational vector, and potentially the stress induced by tissue deformation, because a larger lung volume is gravitationally dependent when supine, but non‐dependent when prone. To evaluate this, 10 normal subjects (six male and four female; age, means ± SD = 27 ± 6 years; height, 171 ± 9 cm; weight, 69 ± 13 kg; forced expiratory volume in the first second/forced expiratory volume as a percentage of predicted, 93 ± 6%) were imaged at functional residual capacity, supine and prone, using magnetic resonance imaging, to quantify regional lung density. We defined regional gravitational stress as the cumulative weight, per unit area, of the column of lung tissue below each point. Gravitational stress was compared between regions of differing inflation to evaluate differences between highly stretched, and thus potentially vulnerable, regions and less stretched lung. Using reference density values for normal lungs at total lung capacity (0.10 ± 0.03 g/ml), regions were classified as highly inflated (density < 0.13 g/ml, i.e., close to total lung capacity), intermediate (0.13 ≤ density < 0.16 g/ml) or normally inflated (density ≥ 0.16 g/ml). Gravitational stress differed between inflation categories while supine (−1.6 ± 0.3 cmH2O highly inflated; −1.4 ± 0.3 cmH2O intermediate; −1.1 ± 0.1 cmH2O normally inflated; P = 0.05) but not while prone (−1.4 ± 0.2 cmH2O highly inflated; −1.3 ± 0.2 cmH2O intermediate; −1.3 ± 0.1 cmH2O normally inflated; P = 0.39), and increased more with height from dependent lung while supine (−0.24 ± 0.02 cmH2O/cm supine; −0.18 ± 0.04 cmH2O/cm prone; P = 0.05). In simulated severe pulmonary oedema, the gradient in gravitational stress increased in both postures (all P < 0.0001), was greater in the supine posture than when prone (−0.57 ± 0.21 cmH2O/cm supine; −0.34 ± 0.16 cmH2O/cm prone; P = 0.0004) and was similar to the gradient calculated from supine computed tomography images in a patient with acute respiratory distress syndrome (−0.51 cmH2O/cm). The non‐dependent lung has greater gravitational stress while supine and might be protected while prone, particularly in the presence of oedema. [ABSTRACT FROM AUTHOR]

Abstract: Background: We investigated in chronic obstructive pulmonary disease (COPD) patients whether a single dose of sildenafil can attenuate the exercise-induced increase in pulmonary artery pressure, thereby allowing augmentation of stroke volume (SV), and improving maximal exercise capacity. Methods: Eighteen COPD patients (GOLD II–IV) underwent right heart catheterization at rest and submaximal exercise. Mean pulmonary artery pressure (mPpa) and cardiac output (CO) were assessed. Resting and exercise measurements were repeated 60min after oral intake of 50mg sildenafil. Also, on different days, patients performed two maximal exercise tests (CPET) randomly, 1h after placebo and after 50mg sildenafil. Results: Five COPD patients had pulmonary hypertension (PH) at rest (mPpa >25mmHg) and six developed PH during exercise (mPpa >30mmHg). In all patients, mPpa increased from rest to submaximal exercise (23±10–35±14mmHg). After sildenafil mPpa at rest was 20±10mmHg, in exercise mPpa was increased less to 30±14mmHg (p<0.01). The reduced augmentation in mPpa was not accompanied by an increased SV and CO. In COPD patients with PH the percentage increase in mPpa to submaximal exercise was 68% before, and 51% after oral intake of sildenafil (p=0.07). In COPD without PH, these values were 46% and 41% (ns), respectively. Maximal exercise capacity and CPET characteristics were unchanged after sildenafil. Conclusion: Regardless of mPpa at rest, sildenafil attenuates the increase in mPpa during submaximal exercise in COPD. This attenuated increase is neither accompanied by enhanced SV and CO, nor by improved maximal exercise capacity. [Copyright &y& Elsevier]

There is increasing recognition of the crucial role of the right ventricle (RV) in determining functional status and prognosis in multiple conditions. The normal RV is anatomically and functionally different from the left ventricle, which precludes direct extrapolation of our knowledge of left-sided physiopathology to the right heart. RV adaptation is largely determined by the level of exposure to hemodynamic overload (both preload and afterload) as well as its intrinsic contractile function. These 3 processes (pressure overload, volume overload, and RV cardiomyopathy) are associated with distinct clinical course and therapeutic approach, although in reality they often coexist in various degrees. The close relationship between the RV and left ventricle (ventricular interdependence) and its coupling to the pulmonary circulation further modulate RV behavior in different clinical scenarios. In this review, the authors summarize current knowledge of RV anatomic, structural, metabolic, functional, and hemodynamic characteristics in both health and disease. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) patients eventually die of right heart failure (RHF). Currently, there is no suitable pre-clinical model to study PAH. Therefore, we aim to develop a right heart dysfunction (RHD) model using the 3-dimensional engineered heart tissue (EHT) approach and cardiomyocytes derived from patient-induced pluripotent stem cells (iPSCs) to unravel the mechanisms that determine the fate of a pressure-overloaded right ventricle. iPSCs from PAH and healthy control subjects were differentiated into cardiomyocytes (iPSC-CMs), incorporated into the EHT, and maintained for 28 days. In comparison with control iPSC-CMs, PAH-derived iPSC-CMs exhibited decreased beating frequency and increased contraction and relaxation times. iPSC-CM alignment within the EHT was observed. PAH-derived EHTs exhibited higher force, and contraction and relaxation times compared with control EHTs. Increased afterload was induced using 2× stiffer posts from day 0. Due to high variability, there were no functional differences between normal and stiffer EHTs, and no differences in the hypertrophic gene expression. In conclusion, under baseline spontaneous conditions, PAH-derived iPSC-CMs and EHTs show prolonged contraction compared with controls, as observed clinically in PAH patients. Further optimization of the hypertrophic model and profound characterization may provide a platform for disease modelling and drug screening. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) remains a challenging condition to diagnose, classify and treat. Current approaches to the assessment of PH include echocardiography, ventilation/perfusion scintigraphy, cross-sectional imaging using computed tomography and magnetic resonance imaging, and right heart catheterisation. However, these approaches only provide an indirect readout of the primary pathology of the disease: abnormal vascular remodelling in the pulmonary circulation. With the advent of newer imaging techniques, there is a shift toward increased utilisation of noninvasive high-resolution modalities that offer a more comprehensive cardiopulmonary assessment and improved visualisation of the different components of the pulmonary circulation. In this review, we explore advances in imaging of the pulmonary vasculature and their potential clinical translation. These include advances in diagnosis and assessing treatment response, as well as strategies that allow reduced radiation exposure and implementation of artificial intelligence technology. These emerging modalities hold the promise of developing a deeper understanding of pulmonary vascular disease and the impact of comorbidities. They also have the potential to improve patient outcomes by reducing time to diagnosis, refining classification, monitoring treatment response and improving our understanding of disease mechanisms., Competing Interests: Conflict of interest: S. Rajagopal reports grants from United Therapeutics, Merck, Janssen and Gossamer Bio, royalties or licences from Polarean, consultancy fees from AERAMI Therapeutics, Liquidia, Gossamer Bio, Merck, Insmed, Polarean, Janssen and Visterra, payment or honoraria for lectures, presentations, manuscript writing or educational events from TotalCME, participation on a data safety monitoring board or advisory board with Aerami Therapeutics, and stock (or stock options) with APIE Therapeutics. H.J. Bogaard reports grants from Janssen, MSD, Novartis and Ferrer. M.S.M. Elbaz reports grants from NIH/NHLBI, support for attending meetings from the World Symposium of Pulmonary Hypertension (WSPH), patents planned, issued or pending (US Patent Application number 17/309,246: noninvasive quantitative flow mapping using a virtual catheter volume), and is a member of the SCMR Science Committee and task force 6 of the 7th WSPH. B.H. Freed reports grants from Cardiovascular Medical Research and Education Fund, and consultancy fees from Change Healthcare. E.J.R. van Beek reports consultancy fees from Aidence (Deep Health) and Lunit, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, and is founder/owner of QCTIS Ltd. D.G. Kiely reports grants from Janssen Pharmaceuticals, National Institute of Health Research Sheffield Biomedical Research Centre and Ferrer, consultancy fees from Janssen Pharmaceuticals, Ferrer, Altavant, MSD, United Therapeutics and Liquidia, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen Pharmaceuticals, Ferrer, Altavant, MSD and United Therapeutics, support for attending meetings from Janssen, Ferrer, MSD and United Therapeutics, participation on a data safety monitoring board or advisory board with Janssen, MSD and Liquidia, and is member of Clinical Reference Group for Specialised Respiratory Medicine (NHS England) and Lead of UK National Audit of Pulmonary Hypertension. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

This article examines technical use of Fitbit during an intervention for pulmonary hypertension (PAH)-patients. Technical issues with the device led to data being unavailable(37.5%). During intervention objective daily physical activity (DPA) decreased and subjective DPA increased. This emphasizes that an assessment of DPA in PAH requires incorporating both objective and subjective measurements., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)