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Background: Pulmonary hypertension (PH), regardless of etiology, remains progressive and incurable despite intensive research for over half a century. Existing therapies have only modestly enhanced survival with the only available “cure” being lung transplantation. The reasons for lack of progress in this area remain unknown but suggest a deficit in understanding the overarching mechanism (s) that drive PH. Recently we reported that the thrombospondin-1 (TSP1)-CD47 ligand receptor pathway is induced in multiple pre-clinical models of PH and human disease. Mice lacking secreted TSP1 are protected from PH. Methods: Wild type and CD47 null mice were challenged with hypoxia and cardiopulmonary assessment performed. Likewise, in cell culture experiments pulmonary arterial vascular smooth muscle cells were exposed to hypoxia and molecular signal transduction assessed. Results: We know report that mice mutated to lack cell receptor CD47 are highly resistant to hypoxia-mediated PH with minimal evidence of pulmonary arterial overgrowth and no right ventricular hypertrophy compared to controls. Hypoxic CD47 null mice demonstrated increased stroke volume and cardiac output compared to a significant deterioration of these functional parameters in wild type controls. Hypoxic wild type animals also displayed concurrent loss of cMyc and upregulation of endothelin-1. In contrast, hypoxic CD47 null animals demonstrated cMyc-mediated suppression of endothelin-1 signaling. Impressively, under basal conditions endothelin-1 and the cognate receptors ETA and ETB where nearly undetectable in CD47 null lungs. Disrupting TSP1-mediated activation of CD47 in monocrotaline treated rats, and in hypoxic pulmonary arterial smooth muscle cell cultures, upregulated cMyc, inhibited endothelin-1 signaling and corrected established PH. Finally, antibody blocking CD47 in lungs from patients with end-stage PH normalized the vasodilation profile of distal pulmonary arteries to acetylcholine and sodium nitroprusside. Conclusions: The above preclinical results suggest CD47 is an important and proximate promoter of PH through cMyc-mediated inhibition of endothelin-1, while results in diseased human PH lung arterioles suggest that CD47 is a clinical target to restore end-stage pulmonary arteriole function. Disclosure: J.S.I. is Chair of the Scientific Advisory Boards and has equity interest in Vasculox, Inc. (St. Louis, MO) and Radiation Control Technologies, Inc. (Rockville, MD). [ABSTRACT FROM AUTHOR]

Background: The number of donors from donation after circulatory determination of death (DCDD) has increased by at least 4-fold over the past decade. This study evaluated the association between the antecedent cardiac arrest status of controlled DCDD donors and the risk of delayed graft function (DGF)., Methods: Using data from the Australia and New Zealand Dialysis and Transplant, the associations between antecedent cardiac arrest status of DCDD donors before withdrawal of cardiorespiratory support, DGF, posttransplant estimated glomerular filtration rate (eGFR), and allograft loss were examined using adjusted logistic, linear mixed modeling, and cox regression, respectively. Among donors who experienced cardiac arrest, we evaluated the association between duration and unwitnessed status of arrest and DGF., Results: A total of 1173 kidney transplant recipients received DCDD kidneys from 646 donors in Australia between 2014 and 2019. Of these, 335 DCDD had antecedent cardiac arrest. Compared with recipients of kidneys from donors without antecedent cardiac arrest, the adjusted odds ratio (95% confidence interval) for DGF was 0.85 (0.65-1.11) among those with kidneys from donors with cardiac arrest. There was no association between antecedent cardiac arrest and posttransplant eGFR or allograft loss. The duration of cardiac arrest and unwitnessed status were not associated with DGF., Conclusions: This focused analysis in an Australian population showed that the allograft outcomes were similar whether DCDD donors had experienced a prior cardiac arrest, with no associations between duration or unwitnessed status of arrest and risk of DGF. This study thus provides important reassurance to transplant programs and the patients they counsel, to accept kidneys from donors through the DCDD pathway irrespective of a prior cardiac arrest., Competing Interests: G.W. is supported by an NHMRC Career Development Fellowship. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Patients with chronic kidney disease (CKD) face a high risk of cardiovascular disease. Previous studies reported that endogenous thrombospondin 1 (TSP1) involves right ventricular remodeling and dysfunction. Here we show that a murine model of CKD increased myocardial TSP1 expression and produced left ventricular hypertrophy, fibrosis, and dysfunction. TSP1 knockout mice were protected from these features. In vitro, indoxyl sulfate is driving deleterious changes in cardiomyocyte through the TSP1. In patients with CKD, TSP1 and aryl hydrocarbon receptor were both differentially expressed in the myocardium. Our findings summon large clinical studies to confirm the translational role of TSP1 in patients with CKD., Competing Interests: This work was supported by a National Health Medical Research Council grant (GNT2007991) to awarded to Dr Rogers, a National Heart Foundation Vanguard Grant (106035) to Drs Rogers and Julovi, and a Westmead Medical Research Foundation grant to Dr Julovi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Patients with CKD continue to experience dramatically reduced life expectancy owing to concomitant CVD, termed CRS. Despite a consensus definition, there has been minimal progress in our understanding of the pathophysiology and no specific therapeutic interventions that improve outcomes. Here we demonstrate that the uremic toxin IS is driving deleterious changes in cardiomyocyte phenotype through the matrix protein TSP1. These findings provide a potential therapeutic target for CRS. TRANSLATIONAL OUTLOOK: Patients with HFpEF are vulnerable to the development of renal dysfunction during treatment for decompensation, and renal-associated mortality is higher in patients with HFpEF. We have identified a novel pathway that drives uremic toxin-induced changes in cardiac pathology through the protein TSP1. Our mechanistic data lend support for testing monoclonal antibodies or peptidic inhibitors that block the actions of TSP1 (and therefore IS), limit development of LVH, and potentially improve survival in CRS., (© 2024 The Authors.)