Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.14817

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.

Blinded by the Light: The Growing Complexity of p53

Hypoxia-Inducible Factors in Physiology and Medicine

ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in Collaboration With the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association

In this commentary, we discuss new observations stating that spliced X-box-binding protein 1 (Xbp1s)-DNA damage-inducible transcript 3 (Ddit3) promotes monocrotaline (MCT)-induced pulmonary hypertension (Jiang et al., Clinical Science (2021) 135(21), https://doi.org/10.1042/CS20210612). Xbp1s-Ddit3 is involved in the regulation of endoplasmic reticulum stress but is also associated with DNA damage repair machinery. Pathologic DNA damage repair mechanisms have emerged as critical determinants of pulmonary hypertension development. We discuss the potential relationship among Xbp1s-Ddit3, DNA damage, and pulmonary hypertension. Although Xbp1s-Ddit3 contributes to the regulation of cell proliferation and apoptosis and the development of vascular lesions, whether Xbp1s is a friend or foe remains controversial.

Commentary on: Xbp1s-Ddit3, DNA damage and pulmonary hypertension.

Intra-Airway Gene Delivery for Pulmonary Hypertension in Rodent Models.


 INTRODUCTION:
 Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis. In cancer, the sustainability of this phenotype required metabolic adaptation (Warburg effect / lipid synthesis) influencing chromatin structure and gene expression. By producing Acetyl coA the ATP Citrate Lyase (ACLY) has emerged as a key player in cancer by favoring Warburg effect, lipid synthesis and histone acetylation.
 
 We hypothesized that ACLY is upregulated in PAH and supports PAH-PASMC proliferation and contributes to PA remodelling.
 
 
 
 METHODS/RESULTS:
 The implication of ACLY in PAH was demonstrated by
 1)
 an upregulation (n=10 p<0.05) of its expression, activation (P-ACLY) and nuclear localization in human PAH lungs, PASMCs and experimental PAH models (sugen/hypoxia, Su/Hx rats and mice) compared to control (immunoblot/immunofluorescence);
 2)
 mice with ACLY deleted in SMCs did not develop Su/Hx-induced PA remodelling and PAH (n=20 p<0.05). Mechanistically, ACLY inhibition (siRNA/BMS) decreased proliferation (Ki67/PCNA) and increased apoptosis (AnnexinV / Survivin) in PAH-PASMCs (n=8 p<0.05). These effects were associated with the inhibition of multiple genes linked to cell cycle, metabolism and lipid synthesis (RNAseq p<0.05 n=6) leading to a decrease (p<0.05) in Warburg effect (LDH, PKM2, P-PDH) and an increase in OCR/ECAR (seahorse). These findings were coupled with an inhibition of the histone acetyl-transferase P300 and histones H3/H4 acetylation. Motif enrichment analyses of transcriptomic datasets identified NFY, NFAT and FOXM1 (all involved in PAH and P300 regulated) as putative transcription factors implicated in ACLY-dependent gene regulation in PAH. This will be confirmed by CHIPseq/ATACseq. In vivo, effects of ACLY inhibitors (BMS/ETC1002) were assessed in rats with Su/Hx-PAH. Both decreased PA pressure, resistance, wall thickness and improved right ventricular functions (n=20; p<0.05) (Echo/catheterization).
 
 
 CONCLUSION:
 We uncovered a novel ACLY-dependent metabolic-transcriptional axis explaining how PASMCs proliferate and survive in PAH. ACLY inhibition is an attractive therapeutic strategy to improve PAH as ETC1002 is clinically advanced.


Abstract 10909: A Novel ATP Citrate Lyase-Dependent Metabolic-Transcriptional Axis in Pulmonary Arterial Hypertension

DHEA and Vascular Health and Functions

https://doi.org/10.1016/j.jacbts.2022.03.015

Sébastien Bonnet

Papers

Commentary on: Xbp1s-Ddit3, DNA damage and pulmonary hypertension.

Intra-Airway Gene Delivery for Pulmonary Hypertension in Rodent Models.

Abstract 10909: A Novel ATP Citrate Lyase-Dependent Metabolic-Transcriptional Axis in Pulmonary Arterial Hypertension

DHEA and Vascular Health and Functions

Reverse Reaction of Nicotinamide Nucleotide Transhydrogenase Promotes ROS Production and Contributes to Right Ventricular Failure