Background and Purpose CX‐5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously we found that CX‐5461 could inhibit pathological arterial remodeling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX‐5461 on experimental pulmonary arterial hypertension (PAH) and PAH‐associated vascular remodeling. Experimental Approach PAH was induced in Sprague‐Dawley rats by monocrotaline or Sugen/hypoxia. Key Results We demonstrated that CX‐5461 was well tolerated for in vivo treatments. CX‐5461 prevented the development of pulmonary arterial remodeling, perivascular inflammation, pulmonary hypertension, and improved survival. More importantly, we showed that CX‐5461 partially reversed pre‐established pulmonary hypertensions. In vitro, CX‐5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells. The beneficial effects of CX‐5461 in vivo and in vitro were associated with increased activation (phosphorylation) of p53. Conclusion and Implications Our results suggest that pharmacological inhibition of Pol I may be a novel therapeutic strategy to treat otherwise drug‐resistant PAH.

Introduction: Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-β superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15.Methods: In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15^high macrophages.Results: We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells by in vitro differentiation with granulocyte-macrophage colony stimulating factor contained a minor population (~1%) of GDF15^high cells. GDF15^high macrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, the in vitro derived GDF15^high macrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, these GDF15^high macrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15 per se was a key mediator of the anti-inflammatory effects of GDF15^high macrophage. Also, we provided evidence showing that GDF15^high macrophages were present in other macrophage-residing human tissues in addition to the lungs. Further scRNA-seq analysis in rat lung macrophages confirmed the presence of a GDF15^high sub-population. However, these data indicated that GDF15^high macrophages in the body were not a uniform population based on their molecular signatures. More importantly, as compared to the in vitro derived GDF15^high macrophage, whether the tissue resident GDF15^high counterpart is also associated with anti-inflammatory functions remains to be determined. We cannot exclude the possibility that the in vitro priming/induction protocol used in our study has a determinant role in inducing the anti-inflammatory phenotype in the resulting GDF15^high macrophage cells.Conclusion: In summary, our results suggest that the GDF15^high macrophage cells obtained by in vitro induction may represent a distinct cluster with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cells in vivo warrants further investigation.

Background: Impedance cardiography (ICG) offers a potential alternative for hemodynamic assessment in pulmonary arterial hypertension (PAH) as a non-invasive technique. Methods: A total of 132 patients who underwent right heart catheterization (RHC) were included. Cardiac output (CO) and stroke volume (SV) measured by thermodilution during RHC (COTD) and ICG (COICG) were compared. The capacity of ICG in PAH risk stratification and clinical deterioration prediction was also analyzed. Results: Ninety-three pre-capillary pulmonary hypertension patients were enrolled, 54 (58.06%) patients belong to Group 1 PAH, and 39 (41.94%) patients were diagnosed with chronic thromboembolic pulmonary hypertension. The mean COTD was 4.93 ± 1.06 L/min, while the COICG was 4.41 ± 1.23 L/min, showing a moderate correlation (r = 0.49, P < .001). In Group 1 PAH patients, the COTD was 5.13 ± 1.10 L/min, and COICG was 4.57 ± 1.22 L/min (r = 0.52, P < .001). Bland–Altman analysis indicated a mean difference of 0.52 L/min and limits of agreement from −1.76 to 2.80 L/min. The mean SVTD was 64.63 ± 17.10 mL, and the SVICG was 60.94 ± 18.03 mL (r = 0.53, P < .001) with a mean difference of 3.69 mL. After a 1-year follow-up, the CIICG and SVIICG showed potential power in predicting clinical deterioration in PAH patients, with area under the curves of 0.76 and 0.81, respectively. Conclusion: Impedance cardiography measured CO and SV presented an acceptable correlation with RHC in PAH patients. Stroke volume index and cardiac index measured by ICG is potent to identify the low-risk status and predict clinical deterioration in PAH patients.

The integrated stress response (ISR) is a conserved cyto-protective mechanism, which has fundamental roles in maintaining cell viability under various conditions when intracellular and/or extracellular homeostasis is disrupted. ISR features phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), leading to a global reduction in protein synthesis. Emerging evidence suggests that activation of ISR may have anti-inflammatory effects. In this concise review, we summarize the current experimental evidence in this regard from both in vitro and in vivo studies. It is suggested that ISR may represent a potential drug target for developing novel anti-inflammatory therapies.

Background: Although pregnancy imposes extra risk in patients with pulmonary arterial hypertension (PAH), hemodynamic characteristics vary between PAH patients with and without cardiac shunts. However, previous studies did not take hemodynamic differences in PAH patients into consideration for pregnancy outcome analysis. We aimed to identify predictors for peripartum outcome of PAH patients without/with cardiac shunt. Methods: We retrospectively analyzed the medical records of PAH gravidae parturiated by cesarean delivery (C-section) from 4 hospitals. Maternal death and major adverse cardiac events (MACEs) occurring during pregnancy or within 6 weeks postpartum were defined as composite end points. Risk factors for end points were analyzed separately in patients with and without cardiac shunt. The effect of general anesthesia on MACEs and maternal death was analyzed considering cardiac shunts. Results: One hundred and eighty-one PAH gravidae were included, of whom 85 had PAH without cardiac shunt and 96 with shunt. Patients who met combined end points were 19/85 in those without shunt compared with 23/96 in those with shunt. The mortality rates were 11.8% and 9.4%, respectively. Both World Health Organization functional class (WHO-FC) III/IV and general anesthesia were predictors for gravidae without shunt, whereas only WHO-FC III/IV was a predictor for gravidae with shunt. General anesthesia increased the MACE risk (odds ratio, 9.000; 95% confidence interval, 2.628–30.820) and maternal mortality (odds ratio, 11.000; 95% confidence interval, 2.595–46.622; P = 0.039) in patients without cardiac shunt but not in those with shunt during C-section. Conclusion: All PAH gravidae with WHO-FC III/IV are at high risk and should receive intensive care. General anesthesia should be avoided during C-section for PAH gravidae without a cardiac shunt.

Background: Exploring accurate and noninvasive methods for detecting pulmonary hypertension (PH) has always been a focal point of research. Owing to its exceptional spatiotemporal resolution, magnetocardiography (MCG) has demonstrated potential value in cardiovascular diseases. Aims: This exploratory study aims to investigate the characteristics of MCG variations in PH patients and evaluate their potential utility in distinguishing healthy subjects from those with PH. Methods: This study analyzed 175 PH patients and 333 healthy subjects who underwent MCG examination. The training cohort consisted of patients with PH previously diagnosed by right heart catheterization (RHC) and age‐frequency‐matched healthy controls (HC). The testing cohort comprised age‐ and frequency‐matched HC and PH patients who underwent both MCG and RHC on the same day. Nine MCG parameters were included. Logistic regression was used to screen for significant parameters and develop a model. Results: By comparing the pseudo‐current density maps, it was found that the current vector at the R‐wave peak of HC points toward the lower‐left quadrant, whereas in PH patients, it points toward the lower‐right quadrant. The MCG detection model demonstrated robust performance, achieving a sensitivity of 86.1% and a specificity of 94.1% in the testing cohort. Compared to the ECG of PH patients, MCG demonstrated greater sensitivity; however, it exhibited slightly lower specificity. Furthermore, MCG can detect PH in patients with normal ECG findings. Conclusion: MCG demonstrates highly promising potential for the noninvasive detection of PH.