Background Maternal iron requirements increase substantially during pregnancy, and ferritin concentrations typically decline as gestation progresses. However, the physiologic significance of this decline remains uncertain, and whether reductions in maternal iron stores relate to birth outcomes is unclear. Objectives To examine associations between maternal ferritin trajectories during pregnancy and postpartum and infant anthropometric outcomes. Methods We conducted a secondary longitudinal analysis of 1,496 mother – infant pairs from the Alberta Pregnancy Outcomes and Nutrition cohort. Serum ferritin was measured longitudinally in the second and third trimesters and at three months postpartum, with limited first-trimester data available. Values below 15 μg/L indicated iron deficiency. Multivariable linear regression assessed associations between inflammation-adjusted third-trimester serum ferritin and infant birthweight and length. Change in serum ferritin between the second and third trimesters (δ ferritin) was examined as a marker of late-gestation iron mobilization. Postpartum serum ferritin was modelled using restricted cubic splines to account for nonlinear associations with birth weight and length. Results Ferritin concentrations declined progressively across pregnancy, with 61% of women classified as iron deficient in the third trimester. Lower inflammation-adjusted third-trimester ferritin was associated with higher birthweight, corresponding to approximately 84g higher birthweight per 2.7 – fold decrease in ferritin (p < 0.001). Women experiencing the largest decline in ferritin between the second and third trimester delivered infants approximately 155 g heavier than those with minimal change (p = 0.001). Higher birthweight was associated with greater odds of postpartum iron deficiency (OR per 1 kg = 1.83; 95% CI: 1.12 – 2.99). Conclusions In this healthy cohort, maternal iron depletion in late pregnancy was associated with higher birthweight, consistent with preferential fetal iron transfer. Women delivering larger infants exhibited higher odds of iron deficiency, suggesting sustained maternal iron depletion following greater fetal iron accretion. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation INV 002855 (MAPS project). Under the grant conditions of the Foundation, a Creative Commons Attribution 4 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. We also would like to acknowledge a research grant from the Canadian Institutes of Health Research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants provided informed consent prior to being included in the study. The project was approved by the University of Calgary Health Research Ethics Board and the University of Alberta Health Research Ethics Biomedical Panel. The present secondary analysis examining maternal iron status during pregnancy and postpartum in relation to birth outcomes was approved by the London School of Hygiene & Tropical Medicine (LSHTM) Ethics Committee (30572/RR/34755, April 2024). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Information about the APrON study is available at www.apronstudy.ca. APrON data are available through Secondary Evidence to Generate Evidence (https://policywise.com/sage/). For more information, contact Principal Investigator, Dr. Nicole Letourneau at Nicole.Letourneau{at}ucalgary.ca. Collaboration or data access inquiries will be considered by the APrON Study team.

Background:Sepsis remains a leading cause of mortality in critical care. Despite extensive preclinical research on sepsis pathophysiology, the development of effective therapies has been largely unsuccessful. Key obstacles include limited construct validity of animal models, insufficient methodological rigor and the lack of collaborative frameworks akin to clinical trials. These issues plague not only sepsis research, but preclinical research in general. The National Preclinical Sepsis Platform (NPSP), an interdisciplinary network under Sepsis Canada, addresses these challenges in sepsis research through multilaboratory, randomized, controlled preclinical studies. NPSP-01 will establish baseline conditions for future investigations using an acute fecal-induced peritonitis model of sepsis. Methods:This randomized, controlled study will evaluate the effect of standard sepsis therapy in a mouse model of sepsis across six centres. Interlaboratory variability and the interaction of biological sex on outcomes will also be examined. C57BL/6 mice of both sexes will be randomized into sham (healthy control) + treatment, sepsis, or sepsis + treatment groups. Sepsis will be induced via intraperitoneal injection of fecal slurry, while sham mice will receive vehicle control. Antibiotics and fluids will be administered to treatment groups at 4 hours post-induction, and mice with be humanely killed at 8 hours post-induction. The primary outcome is plasma interleukin-6 levels. Secondary outcomes include biological (blood gas and chemistry, white blood cell count, bacterial load), clinical (body weight, core temperature, sepsis score, mortality as measured by surrogate humane endpoints), and feasibility measures. Conclusions:NPSP-01 will be the first multilaboratory study of sepsis and represents a shift in preclinical critical illness research, mirroring the rigor of clinical multicenter trials. By addressing procedural standardization, interlaboratory variability, and sex-based differences, this study aims to enhance the reliability and translational relevance of preclinical findings. The outcomes of NPSP-01 will establish foundational data for future investigations and provide a roadmap for rigorous collaborative preclinical studies to accelerate the evaluation of novel sepsis therapies. Registration:PreclinicalTrials.eu PCTE0000552Protocol Version 1.0, October 21, 2024.

Mitochondria play a key role in aging. Here, we measured integrated mitochondrial functions in experimentally evolved lines of the seed beetle Acanthoscelides obtectus that were selected for early (E) or late (L) reproduction for nearly 4 decades. The 2 lines have markedly different lifespans (8 days and 13 days in the E and L lines, respectively). The contribution of the NADH pathway to maximal flux was lower in the L compared to the E beetles at young stages, associated with increased control by complex I. In contrast, the contribution of the Succinate pathway was higher in the L than in the E line, whereas the Proline pathway showed no differences between the lines. Our data suggest that selection of age at reproduction leads to a modulation of complex I activity in mitochondria and that mitochondria are a functional link between evolutionary and mechanistic theories of aging.

Iron deficiency (ID) is common during gestation and in early infancy and has been shown to adversely affect cardiac development and function, which could lead to lasting cardiovascular consequences. Ketone supplementation has been shown to confer cardioprotective effects in numerous disease models. Here, we tested the hypothesis that maternal ketone supplementation during gestation would mitigate cardiac dysfunction in ID neonates. Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and throughout pregnancy. Throughout gestation, iron-restricted dams were given either a daily subcutaneous injection of ketone solution (containing β-hydroxybutyrate [βOHB]) or saline (vehicle). Neonatal offspring cardiac function was assessed by echocardiography at postnatal days (PD)3 and 13. Hearts and livers were collected post-mortem for assessments of mitochondrial function and gene expression profiles of markers oxidative stress and inflammation. Maternal iron restriction caused neonatal anemia and asymmetric growth restriction at all time points assessed, and maternal βOHB treatment had no effect on these outcomes. Echocardiography revealed reduced ejection fraction despite enlarged hearts (relative to body weight) in ID offspring, resulting in impaired oxygen delivery, which was attenuated by maternal βOHB supplementation. Further, maternal ketone supplementation affected biochemical markers of mitochondrial function, oxidative stress and inflammation in hearts of neonates, implicating these pathways in the protective effects conferred by βOHB. In summary, βOHB supplementation confers protection against cardiac dysfunction in ID neonates and could have implications for the treatment of anemic babies.

ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-β in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function.

Iron deficiency (ID) is common during gestation and early infancy and can alter developmental trajectories with lasting consequences on cardiovascular health. Iron plays a critical role in systemic oxygen transport (via hemoglobin) and aerobic respiration (as a component of mitochondrial complexes). Perinatal ID has been shown to cause cardiac dysfunction in neonates, but the mechanisms underlying these changes have not been characterized. Here, we examined the effects of perinatal ID on cardiac mitochondrial function in rats in the early postnatal period. Female rats were fed an iron-restricted or iron-replete diet before and during pregnancy. Offspring hearts were collected postmortem for quantitative shotgun proteomic analysis [postnatal days (PD) 0 and 28] and mitochondrial function was assessed by high-resolution respirometry (at PD 0, 14, and 28). Markers of oxidative stress were measured by fluorescence microscopy and assessment of antioxidant gene expression profiles. Both male and female ID pups had reduced body weight and increased relative heart weights at all time points assessed, despite recovering from anemia by PD28. Proteomics analysis revealed dysregulation of mitochondrial proteins by ID, and these differences were most pronounced in males. In male hearts, ID increased mitochondrial content and decreased normalized mitochondrial respiration through the NADH-pathway, succinate-pathway, and fatty acid oxidation (FAO)-pathway. In conclusion, ID causes changes in cardiac mitochondrial function in neonates, which may reflect inadequate or maladaptive compensation during the transition from intrauterine to extrauterine life. Furthermore, the results presented herein, which were stratified by offspring sex, underscore the need for follow-up studies to directly assess differences in how male and female offspring cope with ID as a perinatal stressor.NEW & NOTEWORTHY Iron deficiency (ID) is the most common nutritional deficiency worldwide and is highly prevalent among pregnant women and young children. ID causes changes in mitochondrial protein expression and function in neonatal hearts, which may contribute to functional impairments. Improving cardiac energy metabolism may represent a novel approach to improve short- and long-term outcomes in infants affected by ID, but sex of the neonate may be an important determinant of treatment efficacy.

We aimed to evaluate fetal and placental oxygen saturation (sO2) in anemic and non-anemic pregnant rats throughout gestation using photoacoustic imaging (PAI). Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and during pregnancy. On gestational days 13, 18, and 21, PAI was coupled with high resolution ultrasound to measure oxygenation of the fetus, whole placenta, mesometrial triangle, as well as the maternal and fetal faces of the placenta. PAI was performed in 3D, which allowed sO2 to be measured within an entire region, as well as in 2D, which enabled sO2 measurements in response to a hypoxic event in real time. Both 3D and 2D PAI were performed at varying levels of FiO2 (fraction of inspired oxygen). Iron restriction caused anemia in dams and fetuses, a reduction in fetal body weight, and an increase in placental weight, but overall had minimal effects on sO2. Reductions in FiO2 caused corresponding reductions in sO2 which correlated to the severity of the hypoxic challenge. Regional differences in sO2 were evident within the placenta and between the placenta and fetus. In conclusion, PAI enables non-invasive measurement of sO2 both rapidly and with a high degree of sensitivity. The lack of overt changes in sO2 levels between control and anemic fetuses may suggest reduced oxygen extraction and utilization in the latter group, which could be attributed to compensatory changes in growth and developmental trajectories.

HomeCirculation ResearchVol. 134, No. 1Reactive Oxygen Species Modulator 1 Plays an Obligate Role in Cardiomyocyte Hypertrophy No AccessResearch ArticleRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessFull TextReactive Oxygen Species Modulator 1 Plays an Obligate Role in Cardiomyocyte Hypertrophy Matthew D. Martens, Claudia D. Holody, Lisa Wells, Heidi L. Silver, Daniela Y. Morales-Llamas, William W. Du, Courtney Reeks, Mostafa Khairy, Huachen Chen, Mourad Ferdaoussi, Stephane L. Bourque, Burton B. Yang, John R. Ussher, Hélène Lemieux, Gavin Y. Oudit, Robert A. Screaton and Jason R.B. Dyck Matthew D. MartensMatthew D. Martens https://orcid.org/0000-0001-9251-6693 Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Claudia D. HolodyClaudia D. Holody https://orcid.org/0000-0003-1479-3809 Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Medicine (C.D.H., H.C., H.L., G.Y.O.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Anesthesiology (C.D.H., S.L.B.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Lisa WellsLisa Wells Sunnybrook Research Institute (L.W., W.W.D., C.R., B.B.Y., R.A.S.), University of Toronto, Ontario, Canada. Department of Biochemistry (L.W., C.R., R.A.S.), University of Toronto, Ontario, Canada. , Heidi L. SilverHeidi L. Silver Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Daniela Y. Morales-LlamasDaniela Y. Morales-Llamas Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , William W. DuWilliam W. Du Sunnybrook Research Institute (L.W., W.W.D., C.R., B.B.Y., R.A.S.), University of Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology (W.W.D., B.B.Y.), University of Toronto, Ontario, Canada. , Courtney ReeksCourtney Reeks https://orcid.org/0009-0002-2451-3532 Sunnybrook Research Institute (L.W., W.W.D., C.R., B.B.Y., R.A.S.), University of Toronto, Ontario, Canada. Department of Biochemistry (L.W., C.R., R.A.S.), University of Toronto, Ontario, Canada. , Mostafa KhairyMostafa Khairy Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Huachen ChenHuachen Chen https://orcid.org/0000-0003-3542-0884 Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Mourad FerdaoussiMourad Ferdaoussi https://orcid.org/0000-0001-7636-0959 Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Faculty Saint-Jean (M.F., H.L.), University of Alberta, Edmonton, Canada. , Stephane L. BourqueStephane L. Bourque Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Medicine (C.D.H., H.C., H.L., G.Y.O.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Anesthesiology (C.D.H., S.L.B.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Burton B. YangBurton B. Yang https://orcid.org/0000-0002-2892-7209 Sunnybrook Research Institute (L.W., W.W.D., C.R., B.B.Y., R.A.S.), University of Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology (W.W.D., B.B.Y.), University of Toronto, Ontario, Canada. , John R. UssherJohn R. Ussher https://orcid.org/0000-0001-9574-5707 Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Faculty of Pharmacy and Pharmaceutical Sciences (J.R.U.), University of Alberta, Edmonton, Canada. , Hélène LemieuxHélène Lemieux Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Medicine (C.D.H., H.C., H.L., G.Y.O.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Faculty Saint-Jean (M.F., H.L.), University of Alberta, Edmonton, Canada. , Gavin Y. OuditGavin Y. Oudit https://orcid.org/0000-0002-9154-9028 Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Medicine (C.D.H., H.C., H.L., G.Y.O.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. , Robert A. ScreatonRobert A. Screaton Correspondence to: Robert A. Screaton, PhD, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room M7 617, Toronto, ON, Canada, M4N 3M5, Email E-mail Address: [email protected] https://orcid.org/0000-0002-4917-9473 Sunnybrook Research Institute (L.W., W.W.D., C.R., B.B.Y., R.A.S.), University of Toronto, Ontario, Canada. Department of Biochemistry (L.W., C.R., R.A.S.), University of Toronto, Ontario, Canada. and Jason R.B. DyckJason R.B. Dyck Jason R.B. Dyck, PhD, 458A Heritage Medical Research Centre, 11207 - 87 Ave NW, Edmonton, AB, Canada, T6G 2S2, Email E-mail Address: [email protected] Cardiovascular Research Centre (M.D.M., H.L.S., D.Y.M.-L., M.K., H.C., M.F., J.R.U., G.Y.O., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Alberta Diabetes Institute (M.D.M., H.L.S., D.Y.M.-L., M.K.,.M.F., J.R.U., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Women and Children's Health Research Institute (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., M.F., S.L.B., J.R.U., H.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Department of Pediatrics (M.D.M., C.D.H., H.L.S., D.Y.M.-L., M.K., S.L.B., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Originally published29 Nov 2023https://doi.org/10.1161/CIRCRESAHA.123.323456Circulation Research. 2024;134:114–116FootnotesFor Sources of Funding and Disclosures, see page 116.Correspondence to: Robert A. Screaton, PhD, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room M7 617, Toronto, ON, Canada, M4N 3M5, Email roblab@gmail.comJason R.B. Dyck, PhD, 458A Heritage Medical Research Centre, 11207 - 87 Ave NW, Edmonton, AB, Canada, T6G 2S2, Email jason.dyck@ualberta.caReferences1. Norton M, Ng AC, Baird S, Dumoulin A, Shutt T, Mah N, Andrade-Navarro MA, McBride HM, Screaton RA. ROMO1 is an essential redox-dependent regulator of mitochondrial dynamics.Sci Signal. 2014; 7:ra10. doi: 10.1126/scisignal.2004374CrossrefMedlineGoogle Scholar2. Richter F, Dennerlein S, Nikolov M, Jans DC, Naumenko N, Aich A, MacVicar T, Linden A, Jakobs S, Urlaub H, et al. ROMO1 is a constituent of the human presequence translocase required for YME1L protease import.J Cell Biol. 2019; 218:598–614. doi: 10.1083/jcb.201806093CrossrefMedlineGoogle Scholar3. Bhandari P, Song M, Dorn GW. Dissociation of mitochondrial from sarcoplasmic reticular stress in Drosophila cardiomyopathy induced by molecularly distinct mitochondrial fusion defects.J Mol Cell Cardiol. 2015; 80:71–80. doi: 10.1016/j.yjmcc.2014.12.018CrossrefMedlineGoogle Scholar4. Chung YM, Kim JS, Yoo YD. A novel protein, Romo1, induces ROS production in the mitochondria.Biochem Biophys Res Commun. 2006; 347:649–655. doi: 10.1016/j.bbrc.2006.06.140CrossrefMedlineGoogle Scholar5. Maulik SK, Kumar S. Oxidative stress and cardiac hypertrophy: a review.Toxicol Mech Methods. 2012; 22:359–366. doi: 10.3109/15376516.2012.666650CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails January 5, 2024Vol 134, Issue 1 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.123.323456PMID: 38018429 Originally publishedNovember 29, 2023 Keywordselectron transportmitochondrial proteinsreactive oxygen speciesrespirationworkloadPDF download Advertisement Subjects Gene Therapy Heart Failure Hypertrophy Oxidant Stress Remodeling

Prenatal hypoxia is associated with placental oxidative stress, leading to impaired fetal growth and an increased risk of cardiovascular disease in the adult offspring; however, the mechanisms are unknown. Alterations in mitochondrial function may result in impaired cardiac function in offspring. In this study, we hypothesized that cardiac mitochondrial function is impaired in adult offspring exposed to intrauterine hypoxia, which can be prevented by placental treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). Cardiac mitochondrial respiration was assessed in 4-month-old rat offspring exposed to prenatal hypoxia (11% O2) from gestational day (GD)15–21 receiving either saline or nMitoQ on GD 15. Prenatal hypoxia did not alter cardiac mitochondrial oxidative phosphorylation capacity in the male offspring. In females, the NADH + succinate pathway capacity decreased by prenatal hypoxia and tended to be increased by nMitoQ. Prenatal hypoxia also decreased the succinate pathway capacity in females. nMitoQ treatment increased respiratory coupling efficiency in prenatal hypoxia-exposed female offspring. In conclusion, prenatal hypoxia impaired cardiac mitochondrial function in adult female offspring only, which was improved with prenatal nMitoQ treatment. Therefore, treatment strategies targeting placental oxidative stress in prenatal hypoxia may reduce the risk of cardiovascular disease in adult offspring by improving cardiac mitochondrial function in a sex-specific manner.

Sepsis remains one of the leading causes of death worldwide. Oncostatin M (OSM), an interleukin (IL)-6 family cytokine, can be found at high levels in septic patients. However, little is known about its role in sepsis. This study aimed to determine if the genetic knockout of OSM receptor (OSMR) type II signaling would improve survival in a murine model of sepsis. Aged (>50 weeks) OSMR type II knockout (KO) mice and wild-type (WT) littermates received an intraperitoneal injection of fecal slurry (FS) or vehicle. The KO mice had better survival 48 h after the injection of FS than the WT mice (p = 0.005). Eighteen hours post-FS injection, the KO mice had reduced peritoneal, serum, and tissue cytokine levels (including IL-1β, IL-6, TNFα, KG/GRO, and IL-10) compared to the WT mice (p < 0.001 for all). Flow cytometry revealed decreased recruitment of CD11b+ F4/80+ Ly6chigh+ macrophages in the peritoneum of KO mice compared to WT mice (34 ± 6 vs. 4 ± 3%, PInt = 0.005). Isolated peritoneal macrophages from aged KO mice had better live E. coli killing capacity than those from WT mice (p < 0.001). Peritoneal lavage revealed greater bacterial counts in KO mice than in WT mice (KO: 305 ± 22 vs. 116 ± 6 CFU (×109)/mL; p < 0.001). In summary, deficiency in OSMR type II receptor signaling provided a survival benefit in the progression of sepsis. This coincided with reduced serum levels of pro-inflammatory (IL-1β, TNFα, and KC/GRO) and anti-inflammatory markers (IL-10), increased bacterial killing ability of macrophages, and reduced macrophage infiltration into to site of infection.

Iron deficiency (ID) is common during gestation and in early infancy and can alter developmental trajectories with lasting consequences on cardiovascular health. While the effects of ID and anemia on the mature heart are well documented, comparatively little is known about their effects and mechanisms on offspring cardiac development and function in the neonatal period. Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and during pregnancy. Cardiac function was assessed in a cohort of offspring on postnatal days (PD) 4, 14, and 28 by echocardiography; a separate cohort was euthanized for tissue collection and hearts underwent quantitative shotgun proteomic analysis. ID reduced body weight and increased relative heart weights at all time points assessed, despite recovering from anemia by PD28. Echocardiographic studies revealed unique functional impairments in ID male and female offspring, characterized by greater systolic dysfunction in the former and greater diastolic dysfunction in the latter. Proteomic analysis revealed down-regulation of structural components by ID, as well as enriched cellular responses to stress; in general, these effects were more pronounced in males. ID causes functional changes in the neonatal heart, which may reflect an inadequate or maladaptive compensation to anemia. This identifies systolic and diastolic dysfunction as comorbidities to perinatal ID anemia which may have important implications for both the short- and long-term cardiac health of newborn babies. Furthermore, therapies which improve cardiac output may mitigate the effects of ID on organ development.

Department of Physiology, Pharmacology and Toxicology, West Virginia University School of Medicine, Morgantown, WV, United States, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada, Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, Canada, Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States

Background Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-h fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2. Results Escalating doses of fecal slurry (0.5–2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS). However, the MSS was poorly associated with progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of early antibiotics within 4 h of inoculation rescued the animals from sepsis compared with late administration of antibiotics after 12 h, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood in the early antibiotic group. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; p < 0.05) for the same dose of fecal slurry (0.75 mg/g) and marked differences in body temperature between groups. Conclusions We demonstrate a systematic approach to optimizing a 72-h FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies.

Abstract ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a risk gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in many congenital heart defects. Here, we demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest leads to a severe congenital cardiac defect termed persistent truncus arteriosus (PTA), ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization and failure to initiate outflow tract septation. Finally, conditional knockout of Ankrd11 in the neural crest leads to impaired Sema3C (Semaphorin 3C) expression, and reduced mTOR (mammalian target of rapamycin) and BMP (Bone Morphogenetic Protein) signaling in the cardiac neural crest cells within the outflow tract. This study identifies Ankrd11 as a novel regulator of neural crest-mediated heart development and function and suggests a mechanism for aberrant heart development in KBG syndrome patients.